WO1995007269A1 - Polar-substituted hydrocarbons - Google Patents

Polar-substituted hydrocarbons Download PDF

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Publication number
WO1995007269A1
WO1995007269A1 PCT/AU1994/000538 AU9400538W WO9507269A1 WO 1995007269 A1 WO1995007269 A1 WO 1995007269A1 AU 9400538 W AU9400538 W AU 9400538W WO 9507269 A1 WO9507269 A1 WO 9507269A1
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WIPO (PCT)
Prior art keywords
group
previously defined
independently
previously
meaning
Prior art date
Application number
PCT/AU1994/000538
Other languages
French (fr)
Inventor
Damian Grobelny
Original Assignee
Narhex Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from AUPM6446A external-priority patent/AUPM644694A0/en
Application filed by Narhex Limited filed Critical Narhex Limited
Priority to DE69433793T priority Critical patent/DE69433793T2/en
Priority to AU76484/94A priority patent/AU697662B2/en
Priority to EP94926731A priority patent/EP0717736B1/en
Priority to JP7508362A priority patent/JPH09503497A/en
Priority to US08/612,894 priority patent/US5888992A/en
Priority to AT94926731T priority patent/ATE267180T1/en
Priority to SK315-96A priority patent/SK31596A3/en
Publication of WO1995007269A1 publication Critical patent/WO1995007269A1/en
Priority to HK98112089A priority patent/HK1011024A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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    • C07C243/10—Hydrazines
    • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
    • C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C243/18—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
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    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
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    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
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    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Definitions

  • the invention relates to certain hydrocarbon derivatives bearing polar substituents and their use in the inhibition of retroviral proteases, for example in the treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS).
  • the invention also relates to processes for preparing such hydrocarbon derivatives bearing polar substituents, to pharmaceutical compositions comprising them and to methods for the treatment or prophylaxis of retroviral infections.
  • the invention also relates to a process for enhancing the water-solubility of a pharmaceutical or veterinary substance.
  • HIV Human immunodeficiency virus
  • HIV PR HIV Proteases
  • aspartyl proteases were first suggested as a potential target for AIDS therapy by Kramer et al. (Science 231, 1580 (1986)). Since that time the potential usefulness of HIV PR inhibitors as effective agents in treatment of AIDS has been widely recognized (for a review of the HIV PR as a therapeutic target see Tomaselli et al.
  • the invention provides compounds which are useful as inhibitors of retroviral proteases, particularly aspartyl proteases and more particularly HIV proteases, and which are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome.
  • retroviral proteases particularly aspartyl proteases and more particularly HIV proteases
  • a first embodiment of the invention is directed to compounds of the general formula (I) or pharmaceutically acceptable salts or prodrugs thereof:
  • Y* is as defined below
  • R 1 , R 3 and R 4 are independently selected from the group consisting of R 6 and a solubilising group Px which is labile in vivo, wherein R 6 is selected from the group consisting of
  • R 20 wherein R 20 is selected from the group consisting of
  • R 21 , R 22 and R 23 independently are selected from hydrogen and R 20 as previously defined, or R 21 and R 22 together, or R 22 and R 23 together form a . saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
  • R 3 and R 4 when present, together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
  • D is selected from O and S,
  • X is selected from the group consisting of Y, S(O) and S(O) 2 wherein Y is as defined below,
  • X* is selected from the group consisting of NR 10 , O and S, wherein R 10 has the meaning of R 6 as previously defined,
  • R 1* is selected from the group consisting of R 1 as previously defined, P(O)(OR 7 )R 8 , S(O) z OR 7 and S(O) z NR 7 R 8 , wherein z is 1 or 2 and R 7 and R 8 independently have the meaning of R 20 as previously defined, or R 7 and R 8 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
  • R 5 and R 5* are independently selected from the group consisting of H, CF 3 , C(D)OR 103 , C(D)SR 103 C(D)NR 103 R 10 4 and R 20 as previously defined, wherein D is as previously defined, and wherein R 103 and R 104 have the meaning of R 6 as previously defined, or R 103 and R 104 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
  • R 5** is selected from hydrogen and R 20 as previously defined;
  • n 0-6;
  • n 0-6 and n+m ⁇ 1;
  • a at each occurrence is independently selected from the group consisting of
  • A* at each occurrence is independently selected from the group consisting of
  • R 12* , R 13* , R 9 and R 9* are independently selected from the group consisting of F, Cl, Br, I and R 5 as previously defined,
  • R 11 has the meaning of R 1 as previously defined
  • R 12 has the meaning of R 6 as previously defined
  • R 13 is selected from the group consisting of
  • R 200 is selected from the group consisting of
  • ONR 60 R 61 wherein D 1 , D 2 , D 3 and D 4 independently have the meaning of D as previously defined, and R 60 , R 61 and R 62 independently have the meaning of R 6 as previously defined or any two or more of R 60 , R 61 and R 62 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
  • L is selected from the group consisting of a bond
  • R 11 and D are as previously defined, R 11* and D* have the meaning of R 11 and D respectively, and z is 1 or 2;
  • R 13** is F, Cl, Br, OR 60 or NR 60 R 60 wherein R 60 and R 61 are as previously defined,
  • B is selected from the group consisting of
  • R 203 and R 203* independently have the meaning of R 6 as previously defined
  • R 14* and R 14** are independently selected from the group consisting of
  • R 40 and R 41 independently have the meaning of R 21 and R 22 as previously defined or R40 and R41 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
  • R14 is selected from the group consisting of F, Cl, Br, I, R 14* as previously defined and R 200 as previously defined,
  • R 17 and R 17* independently have the meaning of R 6 as previously defined
  • D* has the meaning of D as previously defined
  • Z is a samrated or unsaturated (C 2 -C 4 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 14* as previously defined,
  • Z* is a saturated or unsamrated (C 1 -C 3 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 14 * as previously defined,
  • M 1 is selected from the group consisting of OR 15 , SR 15 and NR 15 R 17 , wherein R 15 is selected from the group consisting of:
  • glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and
  • R 17 is as previously defined, or
  • R 15 and R 17 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • M 2 is selected from the group consisting of R 14* as previously defined,
  • R 18 and R 19 independently have the meaning of R 20 as previously defined or
  • R 18 and R 19 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
  • R 18 * and R j9 * together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below;
  • Y is absent or is selected from the group consisting of:
  • D** is selected from the group consisting of a bond, O, S and NR 50 , R 50 has the meaning of R 6 as previously defined, R 51 has the meaning of R 15 as previously defined and R 52 has the meaning of R 20 as previously defined, or R 50 and R 51 , when present, together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
  • R 2 has the meaning of R 6 as previously defined
  • Y* is selected from the group consisting of N
  • D* and D** independently have the meaning of D as
  • R 114* , R 114** , R 115 and R 117* have the meaning of R 14* , R 14** , R 15 and R 17 * respectively, as previously defined;
  • R 50 and R 51 are as previously defined or R 50 and R 51 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below;
  • R 2 * is selected from the group consisting of R 2 as previously defined, Px as previously defined, S(O) z OR 120 and S(O) z NR 120 R 121 , wherein z is 1 or 2;
  • R 33 and R 34 are independently selected from the group consisting of hydrogen and R 20 as previously defined, or R 33 and R 34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
  • R 120 and R 121 independently have the meaning of R 20 as previously defined, or R 120 and R 121 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as
  • R 30 is as previously defined, and
  • R 1 , R 1* , R 2 , R 2* , R 9 , R 11, R 12 , R 13 , R 14 , R 14* , R 17 , R 50 and R 51 may, together with any other group selected from R 1 , R 1 * , R 2 ,
  • R 2* , R 9* , R 10 , R 11 , R 12 , R 13 , R 14 , R 14* , R 17 , R 50 and R 51 form one or more saturated or unsamrated cyclic, bicyclic or fused ring system(s) as defined below, and wherein any tertiary amino nitrogen atom may be replaced by the group , and, wherein any hydroxyl, mercapto or amino group may be protected by a protecting group which is labile in vivo.
  • Compounds of the general formula (I) are useful as inhibitors of retroviral proteases, in particular HIV proteases.
  • One form of the first embodiment of the invention is directed to compounds of the general formula (I') or pharmaceutically acceptable salts or prodrugs thereof:
  • Y* is as defined below
  • R 1 , R 3 and R 4 are independently selected from the group consisting of R 6 and a solubilising group Px which is labile in vivo, wherein R 6 is selected from the group consisting of
  • R 20 wherein R 20 is selected from the group consisting of
  • C 3 -C 18 optionally substituted (C 3 -C 18 )cycloalkyl(C 1 -C 18 )alkyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkynyl, optionally substituted (C 6 -C 24 aryl,
  • R 22 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below, or R 3 and R 4 , when present, together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • D is selected from O and S,
  • X is selected from the group consisting of Y', S(O) and S(O) 2 wherein Y 1 is as defined below,
  • X* is selected from the group consisting of NR 10 , O and S, wherein R 10 has the meaning of R ⁇ as previously defined,
  • R 1* is selected from the group consisting of Ri as previously defined, S(O) z OR 7 and S(O) z NR 7 R 8 , wherein z is 1 or 2 and R 7 and R 8 independently have the meaning of R 20 as previously defined, or R 7 and
  • R 8 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • R 5 and R 5* are independently selected from the group consisting of H, CF 3 , C(D)OR 103 , C(D)SR 103 C(D)NR 103 R 104 and R 20 as previously defined, wherein D is as previously defined, and wherein R 103 and R 104 have the meaning of R 6 as previously defined, or R 103 and R 104 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below;
  • n' is 0-8;
  • n' is 0-8 and n' +m' > 1;
  • A' and A'* are independently at each occurrence selected from the group consisting of O, S, S(O), S(O) 2 , NR 11 , CR 12 R 13 and CR 12 *R 13 *, or two consecutive groups
  • A' -A' or A'*-A'* are a structural unit selected from
  • R 12* , R 13* , R 9 and R 9* are independently selected from the group consisting of F, Cl, Br, I and R 5 as previously defined,
  • R 11 has the meaning of R 1 as previosly defined
  • R 12 has the meaning of R 6 as previously defined
  • R 13 is selected from the group consisting of
  • R 200 wherein R 200 is selected from the group consisting of CN,
  • ONR 60 R 61 wherein D 1 , D 2 , D 3 and D 4 independently have the meaning of D as previously defined, and R 60 , R 61 and R 62 independently have the meaning of R 6 as previously defined or any two or more of R 60 , R 61 and R 62 form part of a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • R 203 and R 203* independently have the meaning of R 6 as previously defined
  • R 14* and R 14** are independently selected from the group consisting of
  • R 21 and R 22 as previously defined or R 40 and R 41 form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • R 14 is selected from the group consisting of F, Cl, Br, I, R 14* as previously defined and R 200 as previously defined,
  • R 17 and R 17* independently have the meaning of R ⁇ as previously defined, D* has the meaning of D as previously defined,
  • Z is a saturated or unsaturated (C 2 -C 4 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 14* as previously defined,
  • Z* is a samrated or unsaturated (C 1 -C 3 )alkylidene radical which is optionally substimted with one or more groups selected from F, Cl, Br, I and R 14* as previously defined,
  • M 1 is selected from the group consisting of OR 15 , SR 15 and NR 15 R 17 , wherein R 15 is selected from the group consisting of:
  • glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and
  • R 17 is as previously defined, or
  • R 15 and R 17 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • R 18 and R19 independently have the meaning of R 20 as previously defined or
  • R 18 and R19 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below, and
  • R 18* and R 19* together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below;
  • R 50 has the meaning of R 6 as previously defined
  • R 51 has the meaning of R 15 as previously defined
  • R 52 has the meaning of R 20 as previously defined
  • R 50 and R 51 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below
  • R 2 has the meaning of R 6 as previously defined
  • Y* is selected from the group consisting of S *
  • D* and D** independently have the meaning of D as
  • R 114* , R 114** , R 115 and R 117* have the meaning of R 14* , R 14** , R15 and R 17* respectively, as previously defined;
  • R 50 and R 51 are as previously defined or R 50 and R 51 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below;
  • R 2 * is selected from the group consisting of R 2 as previously defined, S(O) z OR 120 and S(O) z NR 120 R 121 , wherein z is 1 or 2;
  • R 33 and R 34 are independently selected from the group consisting of hydrogen and R 20 as previously defined, or R 33 and R 34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
  • R 120 and R 121 independently have the meaning of R 20 as previously defined, or R 120 and
  • R 121 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • R 30 is as previously defined, and
  • any group selected from R 1 , R 1* , R 2 , R 2* , R 9 , R 11 , R 12 , R 50 and R 51 may, together with any other group selected from R 1 , R 1* , R 2 , R 2 *, R 9 *, R 10 , R 11 , R 12 , R 50 and R 51 form one or more samrated or unsamrated cyclic, bicyclic or fused ring system(s) as defined below, and wherein any tertiary amino nitrogen atom may be replaced by the group
  • sequence W'-(A') n' -B'-(A'*) m' -V' contains a grouping of three heteroatoms together, one atom of those three heteroatoms is oxidised sulfur in the form of S(O) or S(O) 2 , or oxidised phosphorus in the form of P(O), or the three heteroatoms comprise two nitrogen atoms which form part of a heterocycle, provided that the sequence W'-(A') n '-B'-(A'*) m ' -V' does not contain two oxygen atoms together or three sulfur atoms together;
  • R 81 is selected from the group consisting of hydrogen, -R 100 H,
  • R 101 and R 102 are independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 3 -C 18 )cycloalkyl, optionally substituted
  • R 100 and R 100* are independently divalent radicals derived from a member selected from the group consisting of (C 1 -C 18 )alkyl,
  • R 80 is selected from the group consisting of R 81 as previously defined and a solubilising and/or protecting group Px which is labile in vivo, then at least one of the following applies:
  • R 50 is a group R 53 , wherein R 53 is selected from the group consisting of
  • D* has the meaning of D as previously defined
  • R 21* and R 22* have the meaning of R 2 1 and R 22 respectively, as previously defined,
  • R 55 is selected from the group consisting of optionally substituted (C 1 -C 18 )alkyl(C 6 -C 24 )aryl, optionally substimted
  • n', m', R 1* , R 10 , A', A'*, R 51 and R 2* are as previously defined,
  • R 54 is selected from the group consisting of R55*, C(D*)NR 21* R 22* , C(D*)OR 55* , C(D*)R 55* ,
  • At least one A' or A'* is selected from the group consisting of CR 112 R 13 ,
  • R 112 and R 113 are independently selected from the group consisting of R 55 as previously defined, C(D)OR 21* , C(D)SR 21* , C(D)NR 21* R 22* , F, Cl, Br and I, wherein R 21* and R 22* have the meaning of R 21 and R 22 respectively, as previously defined,
  • n', m', R 1* , R 2* , R 10 , R 1 1 , R 12 , R 12* , R 13 , R 13* , R 50 and R 51 are as previously defined,
  • R 1* is selected from the group consisting of optionally substituted
  • (C 2 -C 18 )alkenyl optionally substimted (C 2 -C 18 )alkynyl, optionally substimted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, optionally substimted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkynyl, optionally substimted (C 6 -C 24 )aryl- (C 2 -C 18 )alkenyl, optionally substimted (C 6 -C 24 )aryl(C 2 -C 18 )alkynyl, optionally substimted (C 2 -C 18 )acyl, wherein the optional substituent is other than amino, optionally substimted (C 6 _C 24 )aryl(C 2 -C 18 )acyl, optionally substimted heterocyclic(C 1 -C 18 )alkyl, optionally substimted hetero
  • R 120 and R 121 are as previously defined, wherein R 90 is selected from the group consisting of (C 3 -C 18 )cycloalkyl,
  • R 91 and R 92 are independently selected from the group consisting of optionally substituted (C 2 -C 18 )alkenyl, optionally substituted (C 2 -C 18 )alkynyl, optionally substimted
  • (C 3 -C 18 )cycloalkyl optionally substimted (C 3 -C 1 g)cycloalkyl(C 1 -C 18 )alkyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, optionally substituted (C 3 -C 18 )cycloalkyl ⁇
  • R 50 and R 51 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
  • At least one group selected from R 2 or R 2* , R 11 , R 12 , R 50 and R 51 together with another group selected from R ⁇ or R 1* , R 10 , R 11 and R 12 forms a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, said ring being substimted with at least one polar group selected from O,
  • R 10* has the meaning of R 10 as previously defined, said polar group being sterically capable of being located within the compound of formula (I) not more than 5 ⁇ ngstrom units from the
  • R 1 *X* and X* is NH and V' is Y* wherein Y* is wherein R 1* is other than H and R 71 and R 72 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, optionally substimted phenyl, optionally substimted naphthyl, optionally substimted phenyl(C 1 -C 2 )alkyl and optionally substimted naphthyl ⁇
  • (a) B' is -CH(OH)- and (A') n is -CH(R 73 )- wherein R 73 is selected from the group consisting of (C 1 -C 6 )alkyl optionally substimted with 1-5 fluorine atoms, (C 3 -C 6 )alkenyl, (C 1 -C 6 )alkoxy-CH 2 -, (CH 2 ) p phenyl, (CH 2 ) p naphthyl, (CH 2 ) p.
  • (C 5 -C 6 )cycloalkyl and (CH 2 ) p indolyl wherein said (CH 2 ) n phenyl, (CH 2 ) n naphthyl, (CH 2 ) n (C 5 -C 6 )cycloalkyl and (CH 2 ) n indolyl are optionally substimted with nitro, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or (C 1 -C 4 )alkylthio and wherein p is 0, 1 or 2, then (A'*) m' is other than wherein R 74 has the meaning of R 73 as previously defined, and
  • (C 1 -C 18 )alkyl includes within its meaning straight and branched chain alkyl groups having from 1 to 18 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylp
  • an alkyl group is (C a -C b )alkyl, in which a is selected from a value presented in the column headed "a” in Table A below at one of entries 1-17, and b has one of the values presented in the column headed "b" at that entry.
  • (C 2 -C 18 )alkenyl includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched.
  • alkenyl groups are vinyl, allyl, 1-methylvinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 2-methylpentenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1,3-octadienyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl,
  • an alkenyl group is (C a -C b )alkenyl, in which a is selected from a value presented in the column headed "a” in Table A above at one of entries 2-17, and b has one of the values presented in the column headed "b" at that entry.
  • (C 2 -C 18 )alkynyl includes within its meamng mono-, di- and poly-acetylenically unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-1-butynyl, n-hexynyl, methyl-pentynyl and
  • an alkynyl group is (C a -C b )alkynyl, in which a is selected from a value presented in the column headed "a” in Table A above at one of entries 2-17, and b has one of the values presented in the column headed "b" at that entry.
  • (C 3 -C 18 )cycloalkyl refers to otionally unsamrated mono-, di- or polycyclic alkyl groups having from 3 to 18 carbon atoms.
  • groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, (C 9
  • a cycloalkyl group is (C a -C b )cycloalkyl, in which a is selected from a value presented in the column headed "a” in Table A above at one of entries 3-17, and b has one of the values presented in the column headed "b" at that entry.
  • (C 3 -C 18 )cycloalkyl(C 1 -C 18 )alkyl refers to a (C 1 -C 18 )alkyl group as defined above, substimted with a (C 3 -C 18 )cycloalkyl group as defined above.
  • cycloalkylalkyl groups include cycloalkyl-loweralkyl groups, such as cycloalkylmethyl, cycloalkylethyl, cycloalkylpropyl, cycloalkylbutyl, cycloalkylisopropyl, cycloalkylisobutyl, cycloalkylpentyl and cycloalkylhexyl, wherein the cycloalkyl is as exemplified in the preceding paragraph.
  • (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl refers to a
  • cycloalkylalkenyl groups include cycloalkyl-loweralkenyl groups, such as cycloalkylethenyl, cycloalkylpropenyl, cycloalkylbutenyl, cycloalkylisobutenyl, cycloalkylpentenyl and cycloalkylhexenyl, wherein the cycloalkyl is as exemplified above under "(C 3 -C 18 )cycloalkyl".
  • (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkynyl refers to a (C 2 -C 18 )alkynyl group as defined above, substituted with a (C 3 -C 18 )cycloalkyl group as defined above.
  • cycloalkylalkynyl groups include cycloalkyl-loweralkynyl groups, such as cycloalkylethynyl, cycloalkylpropynyl, cycloalkylbutynyl, cycloalkylpentynyl and cycloalkylhexynyl, wherein the cycloalkyl is as exemplified above under " (C 3 -C 18 )cycloalkyl".
  • (C 6 -C 24 )aryl refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons having from 6 to 24 carbon atoms.
  • groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, acenaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, indanyl, azulenyl, chrysenyl and the like. In all cases, any available position of the fused or conjugated bicyclic system can be used for attachment to the remainder of the molecule of formula
  • an aryl group is (C a -C b )aryl, in which a is selected from a value presented in the column headed "a” in Table B below at one of entries 1-18, and b has one of the values presented in the column headed "b" at that entry.
  • (C 6 -C 24 )aryl(C 1 -C 18 )alkyl refers to a (C 1 -C 18 )alkyl group substimted with one or more (C 6 -C 24 )aryl groups as previously defined.
  • aryl-loweralkyl groups such as arylmethyl, arylethyl, arylisopropyl, arylpropyl, arylbutyl, arylisobutyl, arylpentyl and arylhexyl, wherein the aryl is as exemplified in the preceding paragraph, such as benzyl, diphenylmethyl, 2-phenylethyl, 1-phenylethyl, naphthylmethyl, 3-phenylpropyl, triphenylmethyl, 1,3-diphenylpropyl, 2- or 3- ⁇ -naphthylpropyl, 2-benzyl-propyl and the like.
  • (C 7 -C 25 )aralkyl refers to an alkyl group substimted with an aryl group, wherein the total number of carbon atoms in the aryl-substimted alkyl group is from 7 to 25.
  • Optional substituents for (C 7 -C 25 )aralkyl are as defined below with respect to (C 6 -C 24 )aryl(C 1 -C 18 )alkyl.
  • (C 6 -C 24 )aryl(C 1 -C 18 )alkenyr' refers to a (C 1 -C 18 )alkenyl group substituted with one or more (C 6 -C 24 )aryl groups as previously defined.
  • aryl-loweralkenyl groups such as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and arylhexenyl, wherein the aryl is as exemplified above under "(C 6 -C 24 )aryl” such as styryl, cinnamyl, 2-naphthylethenyl, l-phenyl-2-methyl-l-propenyl, 2-phenyl-2-butenyl and the like.
  • (C 8 -C 26 )aralkenyl refers to an alkenyl group substimted with an aryl group, wherein the total number of carbon atoms in the arylsubstimted alkenyl group is from 8 to 26.
  • Optional substituents for (C 8 -C 26 )aralkenyl are as defined below with respect to (C 6 -C 24 )aryl(C 2 -C 18 )alkenyl.
  • (C 6 -C 24 )aryl(C 1 -C 18 )alkynyl refers to a (C 1 -C 18 )alkynyl group substimted with one or more (C 6 -C 24 )aryl groups as previously defined.
  • groups are aryl-loweralkenyl groups such as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and arylhexenyl, wherein the aryl is as exemplified above under "(C 6 -C 24 )aryl” such as phenylethynyl and the like.
  • (C 8 -C 26 )aralkynyl refers to an alkynyl group substimted with an aryl group, wherein the total number of carbon atoms in the arylsubstimted alkynyl group is from 8 to 26.
  • Optional substituents for (C 8 -C 26 )aralkynyl are as defined below with respect to (C 6 -C 24 )aryl(C 2 -C 18 )alkynyl.
  • (C 1 -C 18 )acyl refers to a group R 300 C(O)- or R 300 C(S)-, wherein R 300 is selected from the group consisting of hydrogen, (C 1 -C 18 )alkyl, (C 2 -C 18 )alkenyl, (C 2 -C 18 )alkynyl, (C 3 -C 18 )cycloalkyl (C 3 -C 18 )cycloalkyl(C 1 -C 18 )alkyl, (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkynyl, (C 6 -C 24 )aryl, (C 6 -C 24 )aryl(C 1 -C 18 )alkyl, (C 6 -C 24 )aryl(C 2 -C 18 )alkeny
  • an acyl group is (C a -C b )acyl, in which a is selected from a value presented in the column headed "a” in Table A above at one of entries 1-17, and b has one of the values presented in the column headed "b" at that entry.
  • acyl groups include loweralkylcarbonyl such as formyl, acetyl, propionyl, butyryl; loweralkenylcarbonyl such as pivaloyl, acryloyl, vinylacetyl, crotonoyl, 3-pentenoyl, 4-pentenoyl; and loweralkynylcarbonyl such as propioloyl, 2-butynoyl and 3-butynoyl, any of which may be substimted with cycloalkyl, aryl or heterocyclic as exemplified herein, as, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 1-cyclopentenylcarbonyl, cyclopentylacetyl, cyclohexylcarbonyl, 1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl, cyclohexylacetyl
  • heterocyclic refers to any samrated or unsaturated 3- to 16-membered monocyclic, bicyclic or poly cyclic ring containing one or more heteroatom independently selected from oxygen, nitrogen and sulphur.
  • heterocyclic includes any group in which a heterocyclic ring is fused to one or more benzene, naphthalene or cycloalkane rings. Sulfur-containing heterocyclics may be substimted at sulfur with one or two oxygen atoms.
  • heterocyclics are pyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridazinyl, perhydropyridazinyl, pyrazolyl, pyrazoldinyl, 2,3,5,6-tetrahydropyrazinyl, phthalazinyl, 1,2,3,4-tetrahydrophthalazinyl, perhydrophthalazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl, piperidyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolidino, oxazolidinyl, isoxazolyl, isothiazolyl,
  • cyclohexa[b]pyridyl cyclohexa[b]pyrazinyl, cyclohexa[b]pyrimidinyl, cyclohexa[b]-l,4-oxazinyl, cyclohexa[b]1,4-thiazinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperazinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, indolinyl, S,S-dioxo-l,2,3-benzothiadiazolyl, S,S-dioxo-l,2thioxanyl, S,S-dioxo-1,4-thioxanyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroiso
  • heterocyclic or “samrated or unsamrated cyclic, bicyclic or fused ring system”.
  • heterocyclic(C 1 -C 18 )alkyl refers to a (C 1 -C 18 )alkyl group as previously defined, which is substimted with a heterocyclic group as previously defined.
  • groups are heterocyclic-loweralkyl groups such as hetero- cyclicmethyl, heterocyclicethyl, heterocyclicisopropyl, heterocyclicpropyl, heterocyclicbutyl, heterocyclicisobutyl, heterocyclicpentyl and heterocyclichexyl, wherein the heterocyclic is as exemplified in the preceding paragraph.
  • heterocyclic(C 1 -C 18 )alkenyl refers to a (C 1 -C 18 )alkenyl group as previously defined, which is substimted with a heterocyclic group as previously defined.
  • heterocyclic-loweralkenyl groups such as heterocyclicethenyl, heterocyclicpropenyl, heterocyclicbutenyl, heterocyclicisobutenyl, heterocyclicpentenyl and heterocyclichexenyl, wherein the heterocyclic is as exemplified above under "heterocyclic".
  • heterocyclic(C 1 -C 18 )alkynyl refers to a
  • radicals in which one or more of the bonds of the radical from part of a cyclic system, and to such radicals wherein one or more carbon atoms is replaced by O, S or NH.
  • radicals are groups of the structure
  • the term "samrated or unsaturated cyclic, bicyclic or fused ring system” refers to a stable cyclic system of up to 16 carbon atoms, wherein said ring system may contain: for 3- and 4-membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 11-membered rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16-membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur; which ring system may be substimted with one or more substituents independently selected from: R 150 and a group T, where R 150 has the meaning of R 20 as previously defmed, and
  • the term "optionally substimted (C 1 -C 18 )alkyl” refers to a (C 1 -C 18 )alkyl group as defined above wherein one or more hydrogen atoms are replaced by one or more substitutents T as previously defined.
  • substimted (C 1 -C 18 )alkyl groups include hydroxy-loweralkyl such as hydroxymethyl, hydroxyethyl and 3-hydroxypropyl; loweralkoxy-loweralkyl such as methoxy methyl, 2-methoxyethyl, 2,2-dimethoxyethyl and 3-methoxypropyl; aryloxyloweralkyl such as phenoxymethyl, phenoxy ethyl, ⁇ -naphthyloxymethyl and ⁇ -naphthyloxyethyl; arylloweralkoxy-loweralkyl such as benzyloxymethyl, benzyloxyethyl and 3-benzyloxypropyl; halo-loweralkyl such as chloromethyl, trifluoromethyl, 2-fluoro-, 2-chloro-, 2-bromo- or 2-iodo-ethyl, 2,2,2-trifluoro-ethyl, 2,2,2-
  • the term "optionally substimted (C 1 -C 18 )alkenyl” refers to a (C 1 -C 18 )alkenyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defmed.
  • the term "optionally substimted (C 1 -C 18 )alkynyl” refers to a (C 1 -C 18 )alkynyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defined.
  • the term "optionally substimted (C 3 -C 24 )cycloalkyl” refers to a (C 3 -C 24 )cycloalkyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents independently selected from R IV and T as previously defined, wherein R IV is selected from (C 1 -C 1 g)alkyl, (C 2 -C 18 )alkenyl, (C 2 -C 18 )alkynyl, (C 3 -C 18 )cycloalkyl, (C 3 -C 18 )cycloalkyl(C 1 -C 18 )alkyl, (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkynyl, (C 2 -C 18 )acyl,
  • R IV may be substituted with up to six groups independently selected from hydroxy, amino, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, fluoro, chloro, bromo, iodo, carboxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylaminocarbonyl and di(C 1 -C 6 )alkylaminocarbonyl.
  • the term "optionally substimted (C 3 -C 24 )cycloalkyl(C 1 -C 18 )alkenyl” refers to a (C 3 -C 24 )cycloalkyl(C 1 -C 18 )alkenyl group as defined above which are substimted in the cycloalkyl group by a substituent or substitutents independently selected from the substituents defined above for (C 3 -C 24 )cycloalkyl, and/or substimted in the alkenyl group by one or more substituents T as previously defined.
  • the term "optionally substimted (C 3 -C 24 )cycloalkyl(C 1 -C 18 )alkynyl” refers to a (C 3 -C 24 )cycloalkyl(C 1 -C 18 )alkynyl group as defined above which are substituted in the cycloalkyl group by a substituent or substitutents independently selected from the substituents defined above for (C 3 -C 24 )cycloalkyl, and/or substituted in the alkynyl group by one or more substituents T as previously defined.
  • the term "optionally substimted (Cg-C ⁇ aryl” refers to a (C 6 -C 24 )aryl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents independently selected from R v and T*, wherein T* is selected from the group consisting of -F, -Cl, -Br, -I, -CF 3 , -CN, -NCO, -NCS, -OCN, -SCN, -N 3 , -OR', -NR'R", -NR'C(O)R", -NR'C(O)OR", -NR,C(O)NR"R' ' ' , -NO 2 , -SR' , -S(O)R' , -S(O) 2 R', -S(O)OR', -S(O) 2 OR', -S(O)NR'R", -S(O)NR'R
  • substimted aryl groups are loweralkyl-aryl, loweralkenyl-aryl, arylloweralkyl-arylloweralkylcarbonyl-aryl, heterocyclic-aryl and heterocyclicloweralkyl-aryl wherein the aryl group is as exemplified above; halo-aryl such as 4-chlorophenyl, 2,4-dichlorophenyl, 1-chloro-2-naphthyl and 4-chloro-1-naphthyl; hydroxy-aryl such as 2-hydroxyphenyl, 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 2-hydroxy-8-naphthyl, 3,4,5-trihydroxyphenyl and 2,4,5-trihydroxyphenyl; loweralkoxyaryl such as 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl and 1-methoxy-2-naph
  • 1-carbamoyl-2-naphthyl 4-dimethylaminocarbonyl-phenyl, 4-morpholinocarbonylphenyl, 4-(2-pyridylmethoxy)carbonyl-phenyl and 4-benzyloxycarbonyl-phenyl; nitro-aryl such as 4-nitrophenyl and 2,4-dinitrophenyl; amino- or (substituted amino)-aryl such as 4-aminophenyl, 2,4-diaminophenyl, 4-dimethylaminophenyl, 4-anilinophenyl, 2-(2,6-dichloroanilino)-phenyl, 2,4-di-(benzyloxycarbonylamino)-phenyl and 4-(2-quinolinecarbonylamino)-phenyl; and cyano-aryl such as 4-cyanophenyl, as well as aryl groups substimted with two or more of the substituents exemplified above.
  • the term "optionally substituted (C 6 -C 24 )aryl(C 1 -C 18 )alkyl” refers to a (C 6 -C 24 )aryl(C 1 -C 18 )alkyl group as previously defined substituted in the aryl group with one or more substimtents defined above for (C 6 -C 24 )aryl and/or substimted in the alkyl group with one or more substimtents defined above for (C 1 -C 18 )alkyl.
  • aryl-lower-alkyl such as (substituted aryl)methyl, (substituted aryl)ethyl, (substituted aryl)propyl, (substimted aryl)iso-propyl, (substimted aryl)butyl, (substimted aryl)pentyl and (substimted aryl)hexyl, aryl(substituted loweralkyl) such as phenyl(substituted loweralkyl), naphthyl(substituted loweralkyl), biphenyl(substimted loweralkyl), tetrahydronaphthyl (substimted loweralkyl), indenyl(substimted loweralkyl) and indanyl (substimted loweralkyl), and (substimted aryl)(substituted loweralkyl), where
  • the term "optionally substimted (C 6 -C 24 )aryl(C 1 -C 18 )alkenyl” refers to a (C 6 -C 24 )aryl(C 1 -C 18 )alkenyl group as previously defmed substimted in the aryl group with one or more substimtents defmed above for (C 6 -C 24 )aryl and/or substimted in the alkenyl group with one or more substimtents defined above for (C 1 -C 18 )alkyl.
  • the term "optionally substimted (C 6 -C 24 )aryl(C 1 -C 18 )alkynyl” refers to a (C 6 -C 24 )aryl(C 1 -C 18 )alkynyl group as previously defined substimted in the aryl group with one or more substimtents defined above for (C 6 -C 24 )aryl and/or substimted in the alkynyl group with one or more substimtents defined above for (C 1 -C 18 )alkyl.
  • the term "optionally substituted (C 1 -C 18 )acyl” refers to a (C 1 -C 18 )acyl group as previously defmed which may be substimted with one or more groups selected from the substituents defined for (C 1 -C 18 )alkyl, and includes within its meaning an acyl residue of a namrally occurring or synthetic amino acid or azaamino acid, or an acyl residue of a peptide chain containing 2-4 namrally occurring or synthetic amino acids and/or azaamino acids.
  • substimted acyl groups include acyl residues of any of the namrally occurring or synthetic amino acids exemplified herein, hydroxy loweralkanoyl, loweralkoxyloweralkanoyl, acetylloweralkanoyl, cyanoloweralkanoyl, carboxy loweralkanoyl, hydroxycarboxy loweralkanoyl, fluoroloweralkanoyl, chloroloweralkanoyl, bromoloweralkanoyl, thioloweralkanoyl, loweralkanethioloweralkanoyl, aminoloweralkanoyl, loweralkylaminoloweralkanoyl, di-(loweralkylamino)loweralkanoyl, carbamoylloweralkanoyl, loweralkoxy carbonyl, carbamoyl, loweralkylaminocarbonyl and di-(loweralkylamino)carbonyl, where loweralkan
  • optionally substimted heterocyclic refers to a heterocyclic group as previosly defined wherein one or more hydrogen atoms may be replaced with a group selected from the substitutents defmed above with regard to optionally substituted (C 6 -C 24 )aryl.
  • substited heterocyclic groups include loweralkylheterocyclic, arylheterocyclic, aryloxyheterocyclic, loweralkoxyheterocyclic, oxo-heterocyclic, hydroxyheterocyclic, loweralkoxycarbonylheterocyclic and loweralkanoy lheterocyclic .
  • the term "optionally substimted heterocyclic(C 1 -C 18 )alkyl” refers to a heterocyclic(C 1 -C 18 )alkyl group as previously defined substimted in the heterocyclic group with one or more substimtents defined above for heterocyclic and/or substituted in the alkyl group with one or more substitutents defined above for (C 1 -C 18 )alkyl.
  • heterocyclic-lower-alkyl such as (substituted heterocyclic)methyl, (substituted heterocyclic)ethyl, (substimted heterocyclic)propyl, (substimted heterocyclic)iso-propyl, (substimted heterocyclic)butyl, (substimted heterocyclic)pentyl and (substimted heterocyclic)hexyl, heterocyclic(substituted loweralkyl) such as pyrrolyl(substimted loweralkyl), indolyl(substituted loweralkyl), quinolyl(substituted loweralkyl), tetrahydroquinolyl(substituted loweralkyl), pyridyl(substimted loweralkyl), morpholinyl(substituted loweralkyl), piperidinyl(substituted loweralkyl), thiomorpholin
  • the term "optionally substimted heterocyclic(C 1 -C 18 )alkenyl” refers to a heterocyclic(C 1 -C 18 )alkenyl group as previously defmed substimted in the heterocyclic group with one or more substimtents defmed above for heterocyclic and/or substimted in the alkenyl group with one or more substimtents defined above for (C 1 -C 18 )alkenyl.
  • the term "optionally substimted heterocyclic(C 1 -C 18 )alkynyl” refers to a heterocyclic(C 1 -C 18 )alkynyl group as previously defined substimted in the heterocyclic group with one or more substimtents defined above for heterocyclic and/or substituted in the alkynyl group with one or more substitutents defmed above for (C 1 -C 18 )alkynyl.
  • optionally substituted alkylidene refers to an alkylidene radical as previously defined, in which one or more hydrogen atoms is replaced by substituent(s) independently selected from the substituents defined above in connection with “optionally substimted (C 1 -C 18 )alkyl”.
  • the term "namrally occurring or synthetic amino acid” refers to a compound of the formula HN(R 401 )(CH(R 400 )) p COOH, wherein R 400 and R 401 independently have the meaning of R 20 as previously defined, and p is 1, 2 or 3, and wherein R 400 and R 401 , together with the carbon and nitrogen to which they are bound may together form a samrated or unsamrated cyclic, bicyclic or fused ring system.
  • Examples of namrally occurring or synthetic amino acids include alanine, cyclohexylalanine, anthranilic acid, arginine, asparagine, aspartic acid, cysteine, ⁇ -phenylcysteine, cystine, glutamic acid, glutamine, glycine, cyclohexylglycine, tetrahydrofuranylglycine, histidine, homoserine, hydroxyproline, isoleucine, leucine, lysine, 4-azalysine, ⁇ -hydroxylysine, methionine, norleucine, norvaline, ornithine, phenylalanine, 4-aminophenylalanine, 4-carboxyphenylalanine, 4-chlorophenylalanine, phenylglycine, 8-phenylserine, proline, serine, threonine, trans-3-hydroxyproline, trans-4-hydroxyproline, tryptophan, t
  • the term "residue of a namrally occurring or synthetic amino acid” refers to a group of the formula -N(R 401 )(CH(R 400 )) p C(O)-, wherein R 400 , R 401 and p are as defined above with regard to “namrally occurring or synthetic amino acid” .
  • azaamino acid refers to an amino acid in which a -CH(R 400 )- group has been replaced by a group -N(R 401 )-, wherein R 401 has the meaning of R 20 as previously defmed.
  • Suitable pharmaceutically acceptable salts of the compound of formula (I) are, where the compound of formula (I) contains a basic nitrogen atom, acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, hydrobromic or hydriodic, or with pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, methylmaleic, fumaric, malic, citric, lactic, mucic, gluconic, glucoheptonic, glucaric, glucuronic, lactobionic, benzoic, naphthoic, succinic, oxalic, phenylacetic, methanesulphonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethane-1,2-disulfonic, laurylsulfonic, toluenesulphonic, benzene
  • suitable pharmaceutically acceptable salts of the compound of formula (I) are addition salts of pharmaceutically acceptable bases such as lithium, sodium, potassium, ammonium, magnesium, calcium and zinc salts, or salts formed with organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, N-methyl-N-ethylamine, mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, tris(hydroxymethyl)methylamine, N,N-dimethyl-N-(2-hydroxyethyl)-amine, tri-(2-hydroxyethyl)-amine, N-methyl-D-glucamine, or tributylamine.
  • pharmaceutically acceptable bases such as lithium, sodium, potassium, ammonium, magnesium, calcium and zinc salts
  • organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,
  • prodrug refers to a pharmaceutically acceptable derivative of a compound of formula (I) which is transformed into a compound of formula (I) after administration of the prodrug to a living animal or human, and which has enhanced stability, delivery characteristics and/or therapeutic value compared to the compound of formula (I) from which it derives.
  • protecting group refers to a group which may be used temporarily to modify a functional group, for example to prevent that functional group from being affected by, or from undesirably affecting the outcome of, a desired reaction involving another functional group in the molecule and/or to prevent premature metabolism of the compound of formula (I) after administration to a patient before the compound can reach the desired site of action.
  • Suitable protecting groups are described, for example in Greene, T. W., Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 1981) and McOmie, J. F. W., Protective Groups in Organic Chemistry (Plenum Press, London, 1973).
  • suitable protecting groups for hydroxyl or mercapto substituents include substimted methyl ethers, for example, methoxymethyl, benzyloxymethyl, t-butyloxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl, benzyl, allyl, triphenylmethyl and the like, other etherifying groups such as 2-tetrahydrofuryl, 2-tetrahydropyranyl and vinyl, or by acyl and carbonate groups such as formyl, 2,2-dichloroacetyl, 2,2,2-trichloroacetyl, t-butyloxy carbonyl, benzyloxycarbonyl, 4-nitrobenzyloxy carbonyl, and 4-methoxybenzyloxycarbonyl, or by silyl groups such as trimethylsilyl, t-butyldimethylsilyl, tribenzylsilyl, triphenylsilyl and
  • Suitable protecting groups for amino substituents include acyl groups such as formyl, acetyl, 3-phenylpropionyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 4-methoxybenzoyl, t-butyloxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-methoxy benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, (2-pyridyl)methoxycarbonyl, quinoline-2-carbonyl, 2-trimethylsilylethoxycarbonyl, or trimethylsilyl, or an aminoacyl residue.
  • acyl groups such as formyl, acetyl, 3-phenylpropionyl, chloroacetyl, trifluoroacetyl, trichloroacetyl,
  • Suitable protecting groups for carboxyl substituents include esters, for example methyl, ethyl, tert-butyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, methoxymethyl,
  • Suitable protecting groups for carbonyl substituents include acetals such as dimethyl, diethyl, dibutyl and dibenzyl, thioacetals such as S,S-dimethyl and S,S-diethyl, cyclic acetals and thioacetlas such as 1,3-dioxanes, 1,3-dioxolanes, 1,3-oxathiolanes,
  • 1,3-dithianes and 1,3-dithiolanes 1,3-dithianes and 1,3-dithiolanes, and oximes and hydrazones such as O-benzyl oximes,
  • solubilising group Px refers to a group which may be used to derivatise a functional group so as to enhance the solubility of the compound of formula (I) in water or aqueous media.
  • solubilising groups for inclusion in the compound of formula (I) are groups of the formula Px* or salts thereof, where Px* is selected from:
  • R and R' are independently hydrogen or C 1 -C 4 alkyl. Also included within the meaning of Px are groups of the following formulae, wherein Px* and D are as previously defined, and R is H or C 1 -C 4 alkyl:
  • the compound of formula (I) includes two functional groups capable of being derivatised by a solubilising group, the two funtional groups being in sufficiently close proximity to one another, it will be appreciated that certain of the solubilising groups exemplified above are capable of forming cyclic strucmres, for example including the following structural units:
  • X 1 and X 2 are independently selected from O, S and NR 6 wherein R 6 is as previously defined.
  • Solubilising groups in a cyclic strucmre such as those exemplifed above, also fall within the meaning of "solubilising group" as used herein.
  • solubilising group is acidic
  • a salt thereof is typically a salt of an alkali metal or ammonia, such as Na+, K+ or NH 4 +.
  • a salt thereof is typically a salt of a strong inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
  • the solubilising group is a sodium or potassium salt of a phosphate or phosphite residue.
  • Solubilising or protecting groups which are included in the compound of formula (I) must be amenable to hydrolytic or metabolic cleavage in vivo.
  • B is typically selected from the group consisting of
  • Z, Z*, M, M 1 , M 2 , D*, R 14 , R 14* , R 14** , R 15 , R 18 , R 18* , R 19 and R 19* are as previously defmed
  • R 33 , R 34 , R 50 , R 51 and R 2* are as previously defined.
  • the compound of the general formula (I) in this form of the invention has the strucmre represented by formula (IA):
  • R 1* , R 10 , R 12 , R 12* , R 13 and R 13* are as previously defined, B* is selected from the group consisting of
  • x and y are independently 0 or 1 ,
  • B is selected from the group consisting of
  • R 14* , R 14** , R 15 , R 18 and R 19 are as previously defmed and each R 560 is independently hydrogen or (C 1 -C 4 )alkyl
  • R 502 and R 506 are independently a group R 600 , wherein R 600 is selected from the group consisting of hydrogen, C(O)OR 621 , C(O)SR 621 , C(O)NR 621 R 622 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 5 -C 10 )cycloalkyl, (C 5 - C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 5 -C 10 )cycloalkyl(C 2 -C 6 )alkenyl, (C 6 - C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 2 -C 6 )alkenyl, (C 1 - C 6 )acyl, heterocyclic, heterocyclic(C 1 -C 6 )alkyl and heterocyclic(
  • R 501 is selected from the group consisting of R 600 as previously defined, S(O)OR 632 , S(O) 2 R 632 , S(O)NR 632 R 633 , S(O) 2 R 632 R 633 , NH 2 , NHR 631 and NR 631 R 632 , wherein R 631 has the meaning of R 6 as previously defined and R 632 and R 633 independently have the meaning of R 20 as previously defined, or R 501 and R 506 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system, or R 631 and R 632 , or R 632 and R 633 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defmed below,
  • R 512 and R 542 independently have the meaning of R 600 as previously defined
  • R 522 and R 532 are independently selected from the group consisting of R 600 as previously defined, F, Cl, Br and I,
  • R 513 and R 543 are independently selected from the group consisting of R 600 as previously defmed and R 200 as previously defined,
  • R 523 and R 533 are independently selected from the group consisting of R 600 as previously defined, F, Cl, Br, I, and R 200 as previously defined,
  • R 550 has the meamng of R 6 as previously defined and R 551 is selected from the group consisting of R 650 , hydrogen, S(O)OR 632 , S(O) 2 R 632 ,
  • R 650 has the meaning of R 6 as previously defmed and R 632 and R 633 are as previously defined, or R 632 and R 633 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defmed below, or R 550 and one of R 551 and R 502 together form a diazaheterocycle wherein R 550 , R 551 or R 502 and the two nitrogen atoms to which they are bonded are part of a stable 5 to 10- membered ring which may comprise up to two further heteroatoms selected from O, S and N and to which may be fused one or more cycloalkyl, cycloalkenyl, aryl or heterocyclic residues, which diazaheterocycle may be substimted by one or more of the substituents defmed above for "optionally substimted (C 1 -C 18 )alkyl
  • R 512 and R 513 , R 522 and R 523 (when present), R 532 and R 533 (when present), and R 542 and R 543 , together are O; wherein, when B is other than or then at least one of
  • R 655 is selected from the group consisting of (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 2 -C 6 )alkenyl(C 6 -C 10 )aryl, (C 5 -C 10 )cycloalkyl(C 2 -C 6 )alkenyl, (C 5 -C 10 )cycloalkyl(C 6 -C 10 )aryl, acyl(C 6 -C 10 )aryl, heterocyclic(C 1 -C 6 )alkyl, heterocyclic(C 2 -C 6 )alkenyl, heterocyclic(C 6 -C 10 )aryl, C(D*)OR 21* , C(D*)SR 21 * and C(D*)NR 21 *R 22 *, wherein D*, R 21* and R 22* are as previously defined, (ii) at
  • At least one of R 513 and R 543 when present, is selected from the group consisting of R 655 as previously defined, and R 200 as previously defined
  • at least one of R 523 and R 533 when present, is selected from the group consisting of R 655 as previously defmed, F,Cl Br, I and R 200 as previously defined
  • R 550 is a group R 656 , wherein R 656 is selected from the group consisting of (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 2 -C 6 )alkenyl(C 6 -C 10 )aryl, (C 5 - C 10 )cycloalkyl(C 2 -C 6 )alkenyl, (C 5 -C 10 )cycloalkyl(C 6 -C 10 )aryl, acyl(C 6 - C 10 )aryl, heterocyclic(C 1 -C 6 )alkyl, heterocyclic(C 2 -C 6 )alkenyl, heterocyclic(C 6 -C 10 )aryl,
  • R 551 is selected from the group consisting of R 656 as previously defined,
  • R502 is selected from the group consisting of R 65 g as previously defined,
  • R 502 and R 551 are both hydrogen or are both (C 1 -C 6 )acyl
  • R 14* is selected from the group consisting of C(D*)OR 40 , C(D*)SR 40 and C(D*)NR 40 R 41 , wherein R 40 and R 41 are as previously defmed,
  • R 501 is selected from the group consisting of R 656 as previously defmed,
  • R 501 , R 502 , R 506 and R 551 is optionally substituted heterocyclic(C 1 -C 18 )alkyl
  • At least one of R 512 , R 542 , R 522 , R 532 , R 513 , R 543 , R 523 and R 533 is selected from the group consisting of C(O)OR 621 , C(O)SR 621 and C(O)NR 621 R 622 , wherein R 621 and R 622 are as previously defined.
  • each AA is independently a residue of a namrally occurring or synthetic amino acid as herein defined;
  • R 1* , R 1 , X and X* are as previously defmed;
  • Ra to Rj independently are -(CH 2 ) a-6 OPy, wherein a can be 0, 1, 2, 3, 4 or 5, halogen or R 6 , more typically -(CH 2 ) 0 . 3 OPy, fluoro, chloro or R 6* wherein Py is a solubilising group Px as defined herein, R 6 is as previously defined and R 6* is is selected from the group consisting of
  • R 20* wherein R 20* is selected from the group consisting of
  • C 3 -C 8 optionally substimted (C 3 -C 8 )cycloalkyl(C 2 -C 6 )alkenyl, optionally substimted (C 3 -C 8 )cycloalkyl(C 2 -C 6 )alkynyl, optionally substimted (C 6 -C 10 )aryl,
  • R 21 and R 22 independently are selected from hydrogen and R 20* as previously defined, or R 21 and R 22 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as previously defined:
  • D' is O or S
  • each G is independently hydrogen or R 200 as previously defmed and wherein R' d and R' f are R d and R f or, taken together, may be trimethylene or tetramethylene optimally substituted with -C(O)OR; or -C(O)NR i R j ;
  • G is selected from R 1* and X*R 1* ;
  • R a ' is OPy or R 6 as previously defined
  • M 1 is R 6 as previously defined, (CH 2 ) 1- 2 OPy or (CH 2 ) 1-2 NHPy
  • G* is OR 2 or NR i R 2 ;
  • G is hydrogen, R a , R 1* X* or R 1* X*C(R a )(R b )C(O), and wherein R a , R 1* , and the atoms to which they are bound may optionally form a samrated or unsamrated cyclic, bicyclic or fused ring system;
  • R a , R 1* , and the atoms to which they are bound may optionally form a saturated or unsamrated cyclic, bicyclic or fused ring system;
  • W 2 is R 1 X or R 6 as previously defined, and R' is Py or R 6 as previously defmed, or R 1 and Py, taken together with the oxygen atoms to which they are attached form a group selected from , and
  • each L is independently as previously defined and each Pz is independently hydrogen or Py, provided that at least one Pz is Py or, when each Pz is Py, the groups Py, together with the oxygen atoms to which the are bound define a cyclic group selected from
  • Q is O or NR f and G is R 1* or X*R 1* ;
  • each is independently a 5- or 6- membered samrated or unsamrated
  • heterocycle containing a nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, oxygen and sulfur, and wherein R a ' and R b ' independently have the meaning of -(CH 2 ) 0-6 OPy or R 6 , or taken together are O;
  • W 1 is selected from R 1 X and R 1* X*, and Q is selected from O and NR h ;
  • W 1 is selected from R 1 X and R 1* X*, each Pz is independently hydrogen or Py, provided that at least one Pz is Py, and Q is selected from O and NR h ;
  • each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
  • nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, o oxygen and sulfur;
  • R a ' and R j ' are independently selected from R 1 and R 1* , as previously defined; wherein G is selected from , and a saturated or unsaturated
  • ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur;
  • G is selected from hydrogen and R 1* X*, Q is O, S or NH, Q* is O or NH, and G 1 is selected from R 1 and R 1* X*;
  • R 200 is as previously defmed
  • cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur;
  • b is 0, 1 or 2, provided that at least one b is greater than 0, and each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
  • each G* is independently selected from O, S and NR 6 and G is selected from OR 6 , NHR 6 and R 20 ;
  • G is -C(O)- or -CH 2 -
  • G* is R 2 or R 1*
  • G** is -O- or -NR h -
  • Q is -O- or -NR i and Pz is selected from the group consisting of
  • R and R' are independently hydrogen or C 1 -C 4 alkyl, D is O or S and Px* is as previously defined;
  • G is R 1 or R 1* , G* is -O- or -NR f - and Pz is selected from the group consisting
  • R and R' are independently hydrogen or C 1 -C 4 alkyl, D is O or S and
  • G is R 1 or R 1* , and each Q is independently H, -OPz or -NP d Pz, wherein each P z is independently hydrogen or Py, provided that at least one Pz is Py;
  • G is a bond or is -O- or -NR f ;
  • G is absent or X*R 1 * and is a 3 to 10-membered samrated or unsamrated
  • heterocycle containing a nitrogen atom and optionally additionally one to three heteroatoms selected from nitrogen, oxygen and sulfur;
  • Q is selected from -O-, -S- and -NR f- ;
  • R a ' and R b ' have the meamng of R a and R b or R a ' and R b' together are trimethylene or tetramethylene;
  • each Ar is independently (C 6 -C 14 )aryl, R' c and R' d are R c and R d or, taken together, are -C(O)- or -CH(OH)-, and wherein Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from , and ;
  • G is a bond or X as previously defined
  • R g ' and R h ' are R g and R h or together form a samrated or unsamrated cylic, bicylic or fused ring system
  • Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from , and ;
  • G is a bond, O, S or NR j , R g ' and R h ' are R g and R h , or taken together may be - C(O)-, and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from , and ;
  • G is OPy, NHR e , NPyR e or R e ;
  • G and G* are independently a bond, O, S or NH, and R' d and R h ' are Rd and R h or taken together are -CR' 2 - or -CR 2 '-CR 2 '- wherein each R' independently has the meaning of R 6 as previously defined, Q and Q* are independently N or CR 6 , or when Q* is CR 6 then R g and R 6 together may be a double bond;
  • G is -C(O)- or -C(R 6 )(CH 2 ) 0-4 OG* wherein G* is R 6 or Py;
  • G is selected from hydrogen and X*R 1* and wherein represents a 4-10
  • each R z is independently selected from Ri and PyOG* wherein G* is optionally substimted alkylelne, provided that at least one R z is PyOG*, and G is -NR d - or CR d R e -;
  • G is selected from R 1 , XR 1 or X*R 1* and R a and R b taken together may optionally be -C(O)-;
  • B* is a group B, as previously defeined, derivatised with a solubilising group Py;
  • Q 1 and Q 2 are independently selected from O and S, and R' f and R' g are respectively R f and R g or are selected from OR' , SR' and NR h R' wherein R' is H, R i or
  • each G is independently selected from O and NR j , and R' is (CH 2 ) 1 _ 2 OPy or R 6 ;
  • G and G* are independently selected from , and L, wherein L is as previously defined and Q is H or Py, provided that at least one of G and G* is other than L and provided that at least one Q is Py, or wherein two groups OQ taken together are a cyclic group sleeted from , and
  • R x and R y are independently R 6 or (CH 2 ) 1-2 OPy;
  • Still other compounds of the first embodiment are those compounds exemplified in International Patent Application no. WO 93/18006, namely:
  • the compounds of formulae (I) to (LAW) can exist in optically isomeric forms and the present invention includes within its scope all these forms in all proportions including all diastereoisomers and mixtures thereof and all enantiomers, mixtures of enantiomers and racemic mixtures. Where a double bond occurs in the compound of the invention, the double bond may be present in the cis- (Z) or trans- (E) configuration. It will be understood that only compounds of formula (I) with combinations of substituents or functional groups which give rise to stable compounds, are within the scope of the present invention.
  • the compounds of general formula (I) may be prepared by methods known generally in the art. Suitable methods for the synthesis of compounds of formula (I) and intermediates thereof are described, for example, in Houben-Weyl, Methoden der Organischen Chemie; J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley & Sons, New York, 1985); D. C. Liotta and M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley & Sons, Inc., New York, 1991); R. C. Larock, Comprehensive Organic Transformations (VCH, New York, 1989), H. O. House, Modern Synthetic Reactions 2nd Edition (W. A. Benjamin, Inc., Menlo Park, 1972); N. S.
  • a compound of formula (I) may be prepared from synthons W*, ⁇ (A) n -B-(A*) m ⁇ * and V*, wherein each synthon identified thus * is a synthetic precursor of the corresponding portion of the molecule W-(A) n -B-(A*) m -V.
  • a compound of formula (I) may be prepared, for example, in any of the following ways:
  • G is a leaving group such as halogen, typically chlorine, bromine or iodine; a sulfonate such as methanesulfonate, trifluoromethanesulfonate, benzenesulfonate or toluenesulfonate; an alkoxy, thioalkoxy, aryloxy or thioaryloxy group such as ethoxy, methoxy, thiomethoxy or phenoxy; acyloxy such as acetyl, trifluoroacetyl or benzoyl; hydroxy; amino or protonated amino; nitrate; phosphate; borate and the like.
  • halogen typically chlorine, bromine or iodine
  • a sulfonate such as methanesulfonate, trifluoromethanesulfonate, benzenesulfonate or toluenesulfonate
  • these reactions may be carried out in the presence of a base such as triethylamine, pyridine or other tertiary amine, butyllithium, sodium tert-butoxide or similar, and/or a coupling reagent such as a carbodiimide.
  • a base such as triethylamine, pyridine or other tertiary amine, butyllithium, sodium tert-butoxide or similar
  • a coupling reagent such as a carbodiimide.
  • Hal halogen i.e. , fluorine, chlorine, bromine or iodine
  • R represents an alkyl, aryl or aralkyl group, such as t-butyl, phenyl or benzyl.
  • Suitable bases include pyridine, triethylamine and other tertiary amines, alkali metal carbonates and alkali metal hydroxides.
  • the moiety W-(A) n -B-(A*) m - may be represented by R a , in which case R b represents R 50 as previously defined, and R c represents R 2 as previously defmed, or W-(A) n -B-(A*) m - may be represented by R c , in which case R 5 represents R 51 and R a represents R 2 .
  • V is YR 2 where Y is a member of the group
  • the compound of formula (I) may be synthesised by coupling a synthon W-(A) n -B-(A*) m - Z a with a synthon Z b , where Z a includes one of the heteroatoms of Y, and Z b includes the other heteroatom or atoms, as shown in schemes 2a and 2b:
  • Analogous methods may be used to obtain the corresponding thionophosphates and thionophosphonates.
  • the compound of formula (I) may be prepared from a synthon having a ketone or aldehyde function, by condensation with a substimted hy drazine or substimted hydroxylamine corresponding to Y**.
  • (I) may be prepared by oxidation of the corresponding thioether
  • the thioether (IV) may be synthesised by coupling a halide W-(A) n -B-(A*) m -Hal with a thiol R 114* under basic conditions, or by reacting a disulfide R 114* SSR 114* with an organolithium reagent W-(A) n -B-(A*) m -Li derived from the corresponding halide.
  • (I) may be prepared by the Arbuzov reaction as shown in scheme 3:
  • the synthon W-(A) n -B-(A*) m -Z may be prepared by coupling a suitably fiinctionalised fragment W* with a correspondingly fiinctionalised fragment Z*-(A) n -B- (A*) m -Z.
  • the compound of formula (I) may be synthesised by first coupling V to (A) n -B-(A*) m - as described above with reference to schemes 1 to 3, and then coupling the resulting molecule to a fiinctionalised fragment W*.
  • Methods for coupling a precursor of group W with a fiinctionalised fragment Z*-(A) n -B-(A*) m -Z are well known in the art, and include methods analogous to those represented in schemes 1 to 3.
  • W is R 1 X and X is Y
  • the coupling may be achieved as described in schemes 1 to 3 above.
  • W is R 1 X and X is NR 10 , O or S
  • the coupling may be achieved by any of the known methods for the alkylation of amines, and the synthesis of ethers and thioethers, respectively.
  • the coupling may be achieved by reacting a fragment Z*-(A) n -B-(A*) m -Z wherein Z* is a leaving group such as halogen, sulfonate ester, acetate or frialkylammonium salt, with R 1 R 10 NH, R 1 OH or R 1 SH, if necessary in the presence of strong non-nucleophilic base such as butyllithium, sodamide or potassium tert-butoxide.
  • Compounds in which X is S(O) or S(O) 2 may be prepared by the oxidation of the corresponding compound in which X is S.
  • the fragment Z*-(A) n -B-(A*) m -Z may be prepared by methods which depend on the nature of B. Where B is a substimted carbon atom, the fragment may be conveniently prepared from a fragment E-C(O)-E*, in which E is a fragment Z*-(A) n and E* is a fragment (A*) m -Z, as shown in scheme 4:
  • (I) are known compounds or analogs of known compounds which can be prepared by methods analogous to methods used for preparation of the known compounds.
  • the synthesis of known fragments may be found with reference, for example, to
  • a functionalised group E may be coupled to a group E*C(O)H, or a fiinctionalised group E* may be coupled to a group EC(O)H, followed by oxidation.
  • a halide EBr may be coupled to E*C(O)H with an organolithium or organomagnesium reagent derived from EBr, followed by oxidation of the resulting secondary alcohol to the corresponding ketone, if desired.
  • a carboxylic acid EC(O)OH may be converted to an activated derivative, such as an ester or amide: for example an amide obtained by reaction of the carboxylic acid with N,O-dimethyl hydroxy lamine hydrochloride in the presence of a carbodiimide and tertiary base, followed by addition of an organolithium or organomagnesium reagent derived from E*Br, E*C1 or E*I.
  • the fragment Z*-(A) n -B-(A*) m -Z is a substimted amine, phosphine or phosphine oxide, or is an ether, thioether, sulfoxide or sulfone.
  • Substimted amines, ethers, thioethers, sulf oxides and sulfones may be prepared as described above.
  • Secondary or tertiary phosphines may be prepared by alkylation of the corresponding primary or secondary phosphine as described, for example, in J. D. Roberts and M. C. Caserio, Basic Principles of Organic Chemistry (W.A.Benjamin, Inc., New York, 1965).
  • R a and R b have the meaning of R 501 and R 506 as previously defined and R c and R d have the meaning of R 551 and R 502 as previously defined, may be prepared from ethylene cyanohydrin by the method shown in Scheme 5.
  • a substituted compound of formula (IB) may be prepared by the general method of Scheme 5, with the substiments R 512 , R 513 , R 522 , R 523 , R 532 , R 533 , R 542 , R 543 and R 550 being introduced, as desired, into the compounds of formula (Va), (Vb), (Vc) and (Vd) shown in Scheme 5 by the methods illustrated in Scheme 5a.
  • reaction 5a-1 it will be appreciated that the step of introducing the second substituent R' will only be carried out if it is desired that both R 522 and R 523 be other than hydrogen.
  • the reactions shown in 5a-2 and 5a-3 may be repeated, if desired, so as to introduce a second substituent on the carbon atom bearing R" or R"C(O).
  • the second substituent can be the same as or different from the first.
  • this group may be introduced as shown in reaction 5a-3 with respect to compound (Vb).
  • R 522 and R 523 are both hydrogen
  • the reactions shown in 5a-2 and 5a-3 may give mixmres of products and in that case it may be preferable to introduce the desired groups R 532 , R 543 , R 542 and R 543 by replacing the ethylene bromohydrin shown in Scheme 5 with a suitably substimted bromohydrin obtained from the corresponding olefin as shown in Scheme 5b.
  • the nature of the groups Rs 32 , Rs4 3 , Rs4 2 and R 543 will determine the stereochemistry of the addition of HOBr to the olefin and of the opening of the epoxide.
  • the compounds of formula (IB) wherein B is a substimted carbon atom and y is 0 can be prepared by reacting a compound of formula (II), (II A) or (IIB)
  • R 14* , R 501 , R 502 , R 506 , R 512 , R 513 , R 522 , R 523 , R 542 and R 543 have the significance given earlier and Hal is a group selected from -Cl, -Br or -I, with a compound of formula (III)
  • a compound of formula (II), (II A) or (IIB) may be prepared from a ⁇ -amino acid or a ⁇ -amido acid as shown in Scheme 6.
  • a compound of formula IIl may be prepared as shown in Scheme 1a.
  • ⁇ -amino acids may conveniently be prepared by the Mannich reaction of an amine or amide with an enolisable ketone in the presence of formaldehyde or another aldehyde.
  • a compound of formula (IB) wherein x and y are both 0 may be prepared by reacting a compound of formula (EC) or (IID)
  • a compound of formula (IIC) may be prepared from an ⁇ -amino acid by a method analogous to that shown in Scheme 6, such as described in the following:
  • Suitable ⁇ -amino acids may be prepared, for example, by the Strecker synthesis, starting from an appropriate ketone.
  • the overall route to the compound of formula (IIC) is shown in Scheme 7.
  • Other suitable methods are described in Coppola, et al. Asymmetric Synthesis. Construction of Chiral Molecules using Amino Acids (Wiley Interscience, New York, 1987).
  • W is a nitrogen-containing group
  • R 1 and R 10 is a protected amino acid residue
  • the coupling of the protected amino acid residue may be accomplished as shown in Scheme 8, in which the amino acid (designated AA) protecting group is benzyloxycarbonyl, designated Z.
  • AA amino acid
  • Z benzyloxycarbonyl
  • Methods for the formation of peptide bonds and for the protection of peptide residues are described, for example, in Gross and Meienhofer, eds. , The Peptides, (Academic Press, New York, 1983).
  • Suitable other coupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and diphenylphosphoryl azide (DPPA).
  • hydrazine intermediates (III) can be obtained using known methods such as those described in the following:
  • HIV proteases which have hitherto been described, and many other pharmaceutically or veterinarily active substances also typically exhibit low to very low water solubility. This property tends to cause the bioavailability of such substances to be relatively low. There is thus a need for a HIV protease inhibitor having enhanced water solubility.
  • Px is selected from the group consisting of Px*,
  • D is O or S
  • R is H or C 1 -C 4 alkyl
  • Px* is selected from:
  • said functional group being capable of being derivatised with said solubilising group Px.
  • a compound according to the first embodiment includes at least one solubilising group Px as defined above. More generally, a solubilising group in a compound of the first embodiment or in the method of the second embodiment is selected from and .
  • a solubilising group is introduced into the molecule as the last stage of its synthesis.
  • a solubilising group P(O)(OH) 2 may be introduced to a free amino, hydroxy or mercapto group by reaction of the amino, hydroxy or mercapto group with dimethyl chlorophosphate, followed by mild hydrolysis to remove the methyl ester groups.
  • solubilising groups referred to above may be introduced by analogous methods: that is, by reaction of an amino, hydroxy, mercapto or other group capable of being derivatised with a solubilising group, with a reagent PxX' , suitably protected if necessary (for example as methyl or benzyl esters), wherein Px is as defined above and X' is a leaving group such as Cl, Br, OH, OS(O) 2 R and the like, where R is C 1 -C 6 alkyl, for example methyl, C 6 -C 10 aryl, for example phenyl or 4-methylphenyl, or C 7 -C 11 arylalkyl, for example benzyl.
  • a solubilising group P(O)(OH) 2 may be introduced to a free hydroxy group by reaction with phosphorous acid and mercuric salts in the presence of a tertiary amine, as described by Obata and Mukaiyama in J. Org. Chem. , 32, 1063 (1967).
  • an amino, hydroxyl or mercapto group may be reacted with phosphorous acid preferably in the presence of a coupling agent such as dicyclohexylcarbodiimide and pyridine to yield a molecule possessing the solubilising group -OP(O)(OH)H.
  • this group may be oxidised to the corresponding phosphate derivative, for example using bis(trimethylsilyl) peroxide (see Scheme 14 below for an illustration of this method).
  • a further process for the introduction of a group -P(O)(OH) 2 is described in Australian patent application no. 54311/86, and involves the reaction of an amino, hydroxy or mercapto group with certain diesters of amides of phosphorus acid, followed by oxidation and hydrolysis of the resulting intermediate compounds.
  • Suitable reagents for the introduction of a solubilising group -NO 2 are lower alkyl nitrates such as methyl nitrate or ethyl nitrate, and acyl nitrates such as acetyl nitrate or benzoyl nitrate.
  • a third embodiment of the invention is directed to pharmaceutical compositions comprising a compound of formula (I) together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients.
  • a method for inhibiting retroviral proteases in a mammal in need of such inhibition comprising administering to the mammal an effective amount of a compound of the first embodiment or of a composition of the second embodiment.
  • a method for the treatment or prophylaxis of HIV viral infections such as AIDS.
  • composition of the second embodiment may be administered orally, topically, parenterally, e.g. by injection and by intra-arterial infusion, rectally or by inhalation spray.
  • the pharmaceutical composition may be in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, including lyophilised powders, solutions, granules, suspensions, emulsions, syrups and tinctures.
  • Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules.
  • Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents.
  • Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier.
  • suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.
  • Suspensions for oral administration may further comprise dispersing agents and/or suspending agents.
  • Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinyl- pyrrolidone, sodium alginate or cetyl alcohol.
  • Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.
  • the emulsions for oral administration may further comprise one or more emulsifying agents.
  • Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth.
  • the pharmaceutical composition may be in the form of a cream, ointment, gel, jelly, tincture, suspension or emulsion.
  • the pharmaceutical composition may contain pharmaceutically acceptable binders, diluents, disintegrating agents, preservatives, lubricants, dispersing agents, suspending agents and/or emulsifying agents as exemplified above.
  • the compound of formula I or its salt may be prepared in sterile aqueous or oleaginous solution or suspension.
  • Suitable non-toxic parenterally acceptable diluents or solvents include water, Ringer's solution, isotonic salt solution, 5% dextrose in water, buffered sodium or ammonium acetate solution, 1,3-butanediol, ethanol, propylene glycol or polyethylene glycols in mixtures with water.
  • Aqueous solutions or suspensions may further comprise one or more buffering agents. Suitable buffering agents include sodium acetate, sodium citrate, sodium borate or sodium tartrate, for example.
  • Aqueous solutions for parenteral administration are also suitable for administration orally or by inhalation.
  • the compound of formula I is suitably administered in the form of an enema or suppository.
  • a suitable suppository may be prepared by mixing the active substance with a non-irritating excipient which is solid at ordinary temperatures but which will melt in the rectum. Suitable such materials are cocoa butter, waxes, fats, glycerol, gelatin and polyethylene glycols. Suitable enemas may comprise agents as exemplified above with reference to forms for topical administration.
  • an inhalation spray comprising a compound of formula I will be in the form of a solution, suspension or emulsion as exemplified above.
  • the inhalation spray composition may further comprise an inhalable propellant of low toxicity. Suitable propellants include carbon dioxide or nitrous oxide.
  • the dosage form of the compound of formula I will comprise from 0.01 % to
  • dosage forms according to the invention will comprise from 0.1 % to about 10% by weight of the active substance.
  • the compound of formula I may be administered together or sequentially with one or more other active substances known or believed to have anti- viral activity.
  • active substances include AZT, acyclovir, ddC, ddA, trisodium phosphonoformate, castanospermine, rifabutin, ribaviran, bropirimine, phosphonothioate oligodeoxynucleotides, dextran sulfate, ⁇ -interferon and ampligen.
  • Figure 1 is a graph showing the transformation of the compound of Example 5 ("Prodrug”) into the compound of Example 20 of International Patent Application No. PCT/AU93/00103 ("Drug”) in rabbit's blood in vitro.
  • Figures 2 and 3 are graphs showing the transformation of Prodrug into Drug in vivo following intravenous and intramuscular (respectively) administration to a rabbit.
  • Scheme 13 presents an example of a method of preparation of Examples 11 and
  • Scheme 14 presents an example of a method of preparation of compounds of formula shown in Table 4 below, in which the solubilising group Px is P(O)(OH)H or P(O)(OH) 2 :
  • compositions of the third embodiment may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending, grinding, homogenising, suspending, dissolving, emulsifying, dispersing and mixing of the compound of formula (I) together with the selected excipient(s), carrier(s), adjuvant(s) and/or diluent(s).
  • a compound of the first embodiment will usually be administered orally or by injection.
  • a suitable treatment may consist of the administration of a single dose or multiple doses of the compound of formula (I) or of a composition of the third embodiment.
  • the treatment will consist of administering from one to five doses daily of the compound of formula (I) for a period of from one day to several years, up to the lifetime of the patient.
  • the treatment will consist of the administration of the compound of formula (I) for a period of from one day to one year.
  • the administered dosage of the compound of formula I can vary and depends on several factors, such as the condition of the patient. Dosages will range from 0.01mg to 200 mg per kg. Usually, the dose of the active substance will be from 0.01mg to 25 mg per kg of body weight.
  • dosage forms in accordance with the invention are as follows:
  • TLC Thin layer chromotography
  • Step A 4S, 5S-5-benzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy-7-oxo- erhydro-1,2,6-triazepine: Hydrogen chloride gas was bubbled through the solution of 0.51 g (1.26 mmol) of.
  • Step B 4S, 5S-5, 6-dibenzyl-1, 2- (cis-1,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy- 7-oxo-perhydro-1,2,6-triazepine: 4.5 mg (0.15 mmol) of 80% dispersion of sodium hydride in mineral oil was added to a solution of 0.0665 g (0.15 mmol) of the product of Step A in 0.2 ml of dry DMF at room temperature. After stirring for 30 min at room temperamre, 0.0179 ml (0.15 mmol) of benzyl bromide was then added.
  • Step C 4S, 5S-5, 6-Dibenzyl-1, 2- (cis-1, 2-cyclohexane)dimethyl-4-hydroxy- 7-oxo-perhydro-1,2,6-triazepine: A mixmre of 29 mg (0.0543 mmol) of the product of Step B and 0.0426 g (0.163 mmol) of tetrabutylammonium fluoride hydrate in 1 ml of anhydrous acetonitrile was stirred at 45 ⁇ 5°C for 3 hrs and evaporated to dryness.
  • Step A 4S, 5S-5-benzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-l, 2, 6-triazepine:
  • Step B 4S, 5S-1, 5, 6-tribenzyl-2-isopropyl-4-t-butyldimethylsilyloxy- 7-oxo-perhydro-1 , 2, 6-triazepine: A mixture of 0.07 g (0.185 mmol) of the product of Step A and 0.012 g (0.371 mmol) of sodium hydride in 0.2 ml of dry DMF was stirred for 30 min at room temperature, then 0.0441 ml (0.371 mmol) of benzyl bromide was added. The resulting mixmre was stirred overnight and worked up as described in Step B of Example 1.
  • Step C 4S, 5S-1,5, 6-Tribenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-1,2,6-triazepine:
  • Step C the identical process afforded the title compound with 98 % yield as a foam;
  • Rf (A) 0.68;
  • NMR (CDCl 3 ) 1.07, 1.19 (d, d, 6H, isopropyl CH 3 ); 1.58 (s, 1H, OH); 2.6 - 3.15 (m, 5H, CH 2 -3, CH-5, 5-benzyl CH 2 ); 3.2 - 5.3 (m, 6H, isopropyl CH, CH-4, 1,6
  • Example 6 When the product of Example 6 is substimted for t-butyl 3-isopropyl-3-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl carbazate in Example
  • Example 5 The product of Example 5 was converted quantitatively into the corresponding disodium salt by treatment of the free acid with 2 equiv. of 0.2 M sodium bicarbonate and lyophilization of the resulting solution.
  • the retention time of the product of Example 5 was in the range of 3.6 - 3.9 minutes and the retention time of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl carbazate (referred to below as "Drug) was about 6.2 minutes.
  • Detector response was linear from 0.5 to 120 ⁇ M for Prodrug and 0.05 to 50 ⁇ M for Drug.
  • Standards and Sample Processing The standards were prepared by serial dilution of Prodrug or Drug in rabbit blood collected into heparinised tubes.
  • Blood samples were transferred into vials containing 150 units of heparin and stored on ice until processed. The blood samples were then separated by centrifuging at 6000 rpm for 10 min. The plasma samples were frozen and stored at -20°C until they were analysed.
  • Plasma preparation for HPLC analysis An equal volume (100 ⁇ L) of thawed plasma and acetonitrile was stirred with a vortex mixer and allowed to stand at room temperature for 5 minutes, then centrifuged at 14000 rpm for 10 minutes. Samples of the supernantant (50 ⁇ L) were injected into the chromatograph. Transformation of Prodrug into Drug by Blood was established by measurement of prodrug and drug concentrations in plasma following the prodrug incubation in whole rabbit's blood (100 ⁇ M) at 36°C for 19 hours. Fig. 1 shows the concentrations of prodrug and drug under these conditions over 19 hours.
  • the blood plasma concentration of drug was found to be 0.044, 0.141, 0.189, 0.172, 0.164, 0.132, 0.089 and 0.060 ⁇ M, respectively, after 5, 15, 30, 47, 63, 93, 124 and 155 minutes.
  • the blood plasma concentration of drug was found to be 0.137, 0.371, 0.297, 0.242, 0.176, 0.11, 0.071, and 0.050 ⁇ M, respectively, after 5, 15, 30, 45, 60, 94, 123 and 154 minutes.
  • Y* is as defined below
  • R 1 , R 3 and R 4 are independently selected from the group consisting of R 6 and a solubilising group Px which is labile in vivo, wherein R 6 is selected from the group consisting of
  • R 20 wherein R 20 is selected from the group consisting of
  • C 3 -C 18 optionally substituted (C 3 -C 18 )cycloalkyl(C 1 -C 18 )alkyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkynyl, optionally substituted (Cg-C ⁇ aryl,

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Abstract

The invention relates to retroviral protease inhibitors of the general formula (I): W-(A)n-B-(A*)m-V where W, A, B, A*, V, n and m are as defined herein, including related prodrugs of general formula (I) comprising a solubilising group which is labile in vivo.

Description

POLAR-SUBSTITUTED HYDROCARBONS
TECHNICAL FIELD
The invention relates to certain hydrocarbon derivatives bearing polar substituents and their use in the inhibition of retroviral proteases, for example in the treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS). The invention also relates to processes for preparing such hydrocarbon derivatives bearing polar substituents, to pharmaceutical compositions comprising them and to methods for the treatment or prophylaxis of retroviral infections. The invention also relates to a process for enhancing the water-solubility of a pharmaceutical or veterinary substance.
BACKGROUND ART
Human immunodeficiency virus (HIV) is a pathogenic retrovirus causing AIDS and its related disorders. The development of antiviral chemotherapy against AIDS has been the subject of an intense research effort since the discovery of HIV. (For a recent review on molecular targets for AIDS therapy see Mitsua et al, Science, 1990, pp 1533-1544). The HIV Proteases (HIV PR), and aspartyl proteases, were first suggested as a potential target for AIDS therapy by Kramer et al. (Science 231, 1580 (1986)). Since that time the potential usefulness of HIV PR inhibitors as effective agents in treatment of AIDS has been widely recognized (for a review of the HIV PR as a therapeutic target see Tomaselli et al. Chimica Oggi, May 1991, pp 6-27 and Huff J.R., J. Med. Chem. 34, 2314-2327 (1991)). Of the classical transition state mimics for aspartyl proteases, the hydroxy ethylene, dihydroxy ethylene, hydroxyethylamine and phosphinic acid isosteres appear to provide the greatest affinity for HIV PR. Many inhibitors of HIV PR have been shown to have an antiviral activity at concentrations in the nanomolar range in the different cell systems and are described as such in the patent literature.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide compounds useful as retroviral protease inhibitors. It is another object of the present invention to provide pharmaceutical compositions comprising compounds useful for the treatment or prophylaxis of retroviral infections. It is a further object of the present invention to provide methods for the treatment or prophylaxis of retroviral infections, in particular AIDS. Other objects of the present invention are to provide processes for preparing compounds useful as retroviral protease inhibitors, and processes for enhancing the water-solubility of pharmaceutical or veterinary substances, in particular retroviral protease inhibitors.
SUMMARY OF THE INVENTION
The invention provides compounds which are useful as inhibitors of retroviral proteases, particularly aspartyl proteases and more particularly HIV proteases, and which are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome. In the following description of the invention, the teaching of each of the publications mentioned is incorporated herein by reference.
A first embodiment of the invention is directed to compounds of the general formula (I) or pharmaceutically acceptable salts or prodrugs thereof:
W-(A)n-B-(A*)m-V (I)
wherein
W is selected from the group consisting of R1-X-, R1*-X*-, -Y*, -CN, -N=CR5R5*, -C(R5)=NR3, -C(R5)=NOR3, -C(NR3R4)=NR5**, -C(D)OR3, -C(D)SR3 and -C(D)NR3R4, wherein
Y* is as defined below,
R1, R3 and R4 are independently selected from the group consisting of R6 and a solubilising group Px which is labile in vivo, wherein R6 is selected from the group consisting of
hydrogen,
R20, wherein R20 is selected from the group consisting of
optionally substituted (C1-C18)alkyl,
optionally substituted (C2-C18)alkenyl,
optionally substituted (C2-C18)alkynyl,
optionally substituted (C3-C18)cycloalkyl,
optionally substituted (C3-C18)cycloalkyl(C1-C18)alkyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substituted (C6-C24)aryl,
optionally substituted (C6-C24)aryl(C1-C18)alkyl,
optionally substituted (C6-C24)aryl(C2-C18)alkenyl, optionally substituted (C6-C24)aryl(C2-C18)alkynyl, optionally substituted (C 1-C18)acyl,
optionally substituted heterocyclic,
optionally substituted heterocyclictC1-C18)alkyl,
optionally substituted heterocyclic(C2-C18)alkenyl, and optionally substituted heterocyclic(C2-C18)alkynyl
C(D)OR21,
C(D)SR21,
C(D)NR21R22,
C(NR21)R22,
C(NR21)OR22, and
C(NR21)NR22R23, wherein R21, R22 and R23 independently are selected from hydrogen and R20 as previously defined, or R21 and R22 together, or R22 and R23 together form a . saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
or R3 and R4, when present, together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
D is selected from O and S,
X is selected from the group consisting of Y, S(O) and S(O)2 wherein Y is as defined below,
X* is selected from the group consisting of NR10, O and S, wherein R10 has the meaning of R6 as previously defined,
R1* is selected from the group consisting of R1 as previously defined, P(O)(OR7)R8, S(O)zOR7 and S(O)zNR7R8, wherein z is 1 or 2 and R7 and R8 independently have the meaning of R20 as previously defined, or R7 and R8 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
R5 and R5* are independently selected from the group consisting of H, CF3, C(D)OR103, C(D)SR103 C(D)NR103R104 and R20 as previously defined, wherein D is as previously defined, and wherein R103 and R104 have the meaning of R6 as previously defined, or R103 and R104 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
R5** is selected from hydrogen and R20 as previously defined;
n is 0-6;
m is 0-6 and n+m≥1;
A at each occurrence is independently selected from the group consisting of
Figure imgf000005_0001
and a residue of a naturally occurring or synthetic amino acid;
A* at each occurrence is independently selected from the group consisting of
Figure imgf000006_0001
and a residue of a naturally occurring or synthetic amino acid; wherein
R12*, R13*, R9 and R9* are independently selected from the group consisting of F, Cl, Br, I and R5 as previously defined,
R11 has the meaning of R1 as previously defined,
R12 has the meaning of R6 as previously defined,
R13 is selected from the group consisting of
F, Cl, Br, I, R6 as previously defined, and R200, wherein R200 is selected from the group consisting of
CN,
NCO,
NCS,
OCN,
SCN,
N3,
OR60,
SR60,
NR60R61,
D1C(D2)R60,
D1C(D2)D3R60,
D1C(D2)NR60R61,
NR60C(D1)R61,
NR60C(D1)D2R61,
NR60C(D1)NR61R62,
NR60OR61,
amidino,
guanidino,
S(O)R60,
S(O)2D1R60,
S(O)NR60R61,
S(O)2NR60R61,
D 1S(O)R60, D1S(O)2OR60,
D1S(O)NR60R61,
D1S(O)2NR60R61,
P(D1)(D2R60)R61,
P(D1)(D2R60)D3R61,
P(D1)(D2R60)NR61R62,
P(D1)R60R61,
D1P(D2)(D3R60)R61,
D1P(D2)(D3R60)D4R61,
D1P(D2)(D3R60)NR61R62,
D1P(D2)R60R61,
NR60NR61R62 and
ONR60R61, wherein D1, D2, D3 and D4 independently have the meaning of D as previously defined, and R60, R61 and R62 independently have the meaning of R6 as previously defined or any two or more of R60, R61 and R62 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
or R12 and R13 together are selected from the group consisting of =O, =S,
Figure imgf000007_0001
=NOR60, =NR60, -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (C1-C12)alkylidene as defined below and R60 is as previously defined, and
L is selected from the group consisting of a bond,
Figure imgf000007_0002
Figure imgf000008_0001
-CH2- and -CH2-CH2-, wherein R11 and D are as previously defined, R11* and D* have the meaning of R11 and D respectively, and z is 1 or 2;
R13** is F, Cl, Br, OR60 or NR60R60 wherein R60 and R61 are as previously defined,
B is selected from the group consisting of
Figure imgf000008_0002
wherein R203 and R203* independently have the meaning of R6 as previously defined,
R14* and R14** are independently selected from the group consisting of
hydrogen,
R20. as previously defined,
CF3,
C(D*)OR40,
C(D*)SR40 and
C(D*)NR40R41, wherein R40 and R41 independently have the meaning of R21 and R22 as previously defined or R40 and R41 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
R14 is selected from the group consisting of F, Cl, Br, I, R14* as previously defined and R200 as previously defined,
R17 and R17* independently have the meaning of R6 as previously defined,
D* has the meaning of D as previously defined,
Z is a samrated or unsaturated (C2-C4)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
Z* is a saturated or unsamrated (C1-C3)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
M1 is selected from the group consisting of OR15, SR15 and NR15R17, wherein R 15 is selected from the group consisting of:
Px as previously defined, and
R6 as previously defined, and
a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and
R17 is as previously defined, or
R15 and R17 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
M and M* are independently selected from the group consisting of M1 as previously defined, OCN, SCN, YR2, Y* and N=CR30R31 , wherein Y, Y* and R2 are as defined below, and R30 and R31 independently have the meaning of R20 as previously defined,
M2 is selected from the group consisting of R14* as previously defined,
-CR30*=Y** and -CR30*=NR17*, where Y** is as defined below, R30* has the meaning of R20 as previously defined, and R17* is as previously defined,
R18 and R19 independently have the meaning of R20 as previously defined or
R18 and R19 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
R18* and Rj9* together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below;
V is selected from the group consisting of YR2, Y* and C(R30)=Y**, wherein
Y is absent or is selected from the group consisting of:
Figure imgf000010_0001
wherein D** is selected from the group consisting of a bond, O, S and NR50, R50 has the meaning of R6 as previously defined, R51 has the meaning of R15 as previously defined and R52 has the meaning of R20 as previously defined, or R50 and R51, when present, together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and
R2 has the meaning of R6 as previously defined,
Y* is selected from the group consisting of N
Figure imgf000011_0001
, wherein D* and D** independently have the meaning of D as
Figure imgf000011_0002
previously defined; R114*, R114**, R115 and R117* have the meaning of R14*, R14**, R15 and R17* respectively, as previously defined; R50 and R51 are as previously defined or R50 and R51 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below; R2* is selected from the group consisting of R2 as previously defined, Px as previously defined, S(O)zOR120 and S(O)zNR120R121, wherein z is 1 or 2; R33 and R34 are independently selected from the group consisting of hydrogen and R20 as previously defined, or R33 and R34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and R120 and R121 independently have the meaning of R20 as previously defined, or R120 and R121 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
R30 is as previously defined, and
Y** is selected from =N-NR115R117 and =N-OR115, wherein R115 and R117 have the meaning of R15 and R6 respectively, as previously defined, or R115 and R117 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,
and wherein any group selected from R1, R1*, R2, R2*, R9, R11, R12, R13, R14, R14*, R17, R50 and R51 may, together with any other group selected from R1, R1 *, R2,
R2*, R9*, R10, R11, R12, R13, R14, R14*, R17, R50 and R51 form one or more saturated or unsamrated cyclic, bicyclic or fused ring system(s) as defined below, and wherein any tertiary amino nitrogen atom may be replaced by the group
Figure imgf000012_0001
, and, wherein any hydroxyl, mercapto or amino group may be protected by a protecting group which is labile in vivo.
Compounds of the general formula (I) are useful as inhibitors of retroviral proteases, in particular HIV proteases.
One form of the first embodiment of the invention is directed to compounds of the general formula (I') or pharmaceutically acceptable salts or prodrugs thereof:
W'-(A')n'-B'-(A'*)m'-V' (I')
wherein
W' is selected from the group consisting of R1-X-, R1*-X*-, -Y*, -CN, -N=CR5R5*, -C(R5)=NR3, -C(R5)=NOR3, -C(D)OR3, -C(D)SR3 and -C(D)NR3R4, wherein
Y* is as defined below,
R1, R3 and R4 are independently selected from the group consisting of R6 and a solubilising group Px which is labile in vivo, wherein R6 is selected from the group consisting of
hydrogen,
R20, wherein R20 is selected from the group consisting of
optionally substituted (C1-C18)alkyl,
optionally substituted (C2-C18)alkenyl,
optionally substituted (C2-C18)alkynyl,
optionally substituted (C3-C18)cycloalkyl,
optionally substituted (C3-C18)cycloalkyl(C1-C18)alkyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substituted (C6-C24 aryl,
optionally substituted (C6-C24)aryl(C 1-C18)alkyl,
optionally substituted (C6-C24)aryl(C2-C18)alkenyl, optionally substituted (C6-C24)aryl(C2-C18)alkynyl, optionally substituted (C1-C18)acyl,
optionally substituted heterocyclic,
optionally substituted heterocyclic(C1-C18)alkyl,
optionally substituted heterocyclic(C2-C18)alkenyl, and optionally substituted heterocyclic(C2-C18)alkynyl
C(D)OR21,
C(D)SR21, and C(D)NR21R22, wherein R21 and R22 independently are selected from hydrogen and R20 as previously defined, or R21 and
R22 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below, or R3 and R4, when present, together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
D is selected from O and S,
X is selected from the group consisting of Y', S(O) and S(O)2 wherein Y1 is as defined below,
X* is selected from the group consisting of NR10, O and S, wherein R10 has the meaning of R^ as previously defined,
R1* is selected from the group consisting of Ri as previously defined, S(O)zOR7 and S(O)zNR7R8, wherein z is 1 or 2 and R7 and R8 independently have the meaning of R20 as previously defined, or R7 and
R8 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
R5 and R5* are independently selected from the group consisting of H, CF3, C(D)OR103, C(D)SR103 C(D)NR103R104 and R20 as previously defined, wherein D is as previously defined, and wherein R103 and R104 have the meaning of R6 as previously defined, or R103 and R104 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below;
n' is 0-8;
m' is 0-8 and n' +m' > 1;
A' and A'* are independently at each occurrence selected from the group consisting of O, S, S(O), S(O)2, NR11, CR12R13 and CR12*R13*, or two consecutive groups A' -A' or A'*-A'* are a structural unit selected from
Figure imgf000013_0001
— C≡≡C— , wherein
and
R12*, R13*, R9 and R9* are independently selected from the group consisting of F, Cl, Br, I and R5 as previously defined,
R11 has the meaning of R1 as previosly defined,
R12 has the meaning of R6 as previously defined,
R13 is selected from the group consisting of
F, Cl, Br, I, R6 as previously defined, and R200 wherein R200 is selected from the group consisting of CN,
NCO,
NCS,
OCN,
SCN,
N3,
OR60,
SR60,
NR60R61,
D1C(D2)R60,
D1C(D2)D3R60,
D1C(D2)NR60R61,
NR60C(D1)R61,
NR60C(D1)D2R61,
NR60C(D1)NR61R62,
NR60OR61,
amidino,
guanidino,
S(O)R60,
S(O)2D1R60,
S(O)NR60R61,
S(O)2NR60R61,
D1S(O)R60,
D1S(O)2OR60,
D 1S(O)NR60R61,
D1S(O)2NR60R61,
P(D1)(D2R60)R61,
P(D1)(D2R60)D3R61,
P(D1)(D2R60)NR61R62,
P(D1)R60R61,
D1P(D2)(D3R60)R61,
D1P(D2)(D3R60)D4R61,
D1P(D2)(D3R60)NR61R62,
D1P(D2)R60R61,
NR60NR61R62 and
ONR60R61, wherein D1, D2, D3 and D4 independently have the meaning of D as previously defined, and R60, R61 and R62 independently have the meaning of R6 as previously defined or any two or more of R60, R61 and R62 form part of a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below,
or R12 and R13 together are selected from the group consisting of =O, =S, =NOR60, =NR60, -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (C1-C12)alkylidene as defined below and R60 is as previously defined;
selected from the group consisting of
Figure imgf000015_0001
wherein R203 and R203* independently have the meaning of R6 as previously defined,
R14* and R14** are independently selected from the group consisting of
hydrogen,
R20 as previously defined,
CF3, C(D*)OR4o,
C(D*)SR40 and
C(D*)NR40R41, wherein R40 and R41 independently have the meaning of
R21 and R22 as previously defined or R40 and R41 form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
R14 is selected from the group consisting of F, Cl, Br, I, R14* as previously defined and R200 as previously defined,
R17 and R17* independently have the meaning of Rβ as previously defined, D* has the meaning of D as previously defined,
Z is a saturated or unsaturated (C2-C4)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
Z* is a samrated or unsaturated (C1-C3)alkylidene radical which is optionally substimted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
M1 is selected from the group consisting of OR15, SR15 and NR15R17, wherein R15 is selected from the group consisting of:
Px as previously defined,
R6 as previously defined, and
a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and
R17 is as previously defined, or
R15 and R17 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
M and M* are independently selected from the group consisting of M1 as previously defined, OCN, SCN, Y'R2, Y* and N=CR30R31, wherein Y', Y* and R2 are as defined below, and R30 and R31 independently have the meaning of R20 as previously defined,
M2 is selected from the group consisting of R14* as previously defined, -CR30*=Y** and -CR30*=NR17*, where Y** is as defined below, R30* has the meaning of R20 as previously defined, and R17* is as previously defined,
R18 and R19 independently have the meaning of R20 as previously defined or
R18 and R19 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below, and
R18* and R19* together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below; V' is selected from the group consisting of Y'R2, Y* and C(R30)=Y**, wherein Y' is selected from the group consisting of
O
Figure imgf000017_0001
wherein R50 has the meaning of R6 as previously defined, R51 has the meaning of R15 as previously defined and R52 has the meaning of R20 as previously defined, or R50 and R51 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below, and
R2 has the meaning of R6 as previously defined,
Y* is selected from the group consisting of S *
Figure imgf000018_0001
, wherein D* and D** independently have the meaning of D as
Figure imgf000018_0002
previously defined; R114*, R114**, R 115 and R117* have the meaning of R14*, R14**, R15 and R17* respectively, as previously defined; R50 and R51 are as previously defined or R50 and R51 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below; R2* is selected from the group consisting of R2 as previously defined, S(O)zOR120 and S(O)zNR120R121 , wherein z is 1 or 2; R33 and R34 are independently selected from the group consisting of hydrogen and R20 as previously defined, or R33 and R34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and R120 and R121 independently have the meaning of R20 as previously defined, or R120 and
R121 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
R30 is as previously defined, and
Y** is selected from =N-NR115R117 and =N-OR115, wherein R115 and R117 have the meamng of R15 and R6 respectively, as previously defined, or R115 and R117 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defined below,
and wherein any group selected from R1, R1*, R2, R2*, R9, R11, R12, R50 and R51 may, together with any other group selected from R 1, R1*, R2, R2*, R9*, R10, R11, R12, R50 and R51 form one or more samrated or unsamrated cyclic, bicyclic or fused ring system(s) as defined below, and wherein any tertiary amino nitrogen atom may be replaced by the group
Figure imgf000018_0003
and, where the sequence W'-(A')n'-B'-(A'*)m'-V' contains a grouping of three heteroatoms together, one atom of those three heteroatoms is oxidised sulfur in the form of S(O) or S(O)2, or oxidised phosphorus in the form of P(O), or the three heteroatoms comprise two nitrogen atoms which form part of a heterocycle, provided that the sequence W'-(A')n'-B'-(A'*)m '-V' does not contain two oxygen atoms together or three sulfur atoms together;
and wherein (a) when W' is R1*X* wherein X* is NR10, and V' is Y* wherein Y* is
Figure imgf000019_0001
, and B' is or
Figure imgf000019_0003
Figure imgf000019_0002
wherein R81 is selected from the group consisting of hydrogen, -R100H,
-R100C(O)OR101 , -R100C(O)NR101R102, -R100NR102C(O)R100* and -R100C(O)R100*,
wherein R101 and R102 are independently selected from the group consisting of hydrogen, optionally substituted (C1-C18)alkyl, optionally substituted (C3-C18)cycloalkyl, optionally substituted
(C3-C18)cycloalkyl-(C1-C18)alkyl, optionally substituted (C6-C24)aryl, optionally substituted (C7-C25)aralkyl, optionally substimted (C2-C18)alkenyl, optionally substimted (C8-C26)-aralkenyl, optionally substimted (C2-C18)-alkynyl, optionally substimted (C8-C26)- aralkynyl and optionally substimted heterocyclic, and wherein R100 and R100* are independently divalent radicals derived from a member selected from the group consisting of (C1-C18)alkyl,
(C3-C18)cycloalkyl, (C3-C18)cycloalkyl(C1-C18)alkyl, (C6-C24)aryl,
(C7-C25)aralkyl, (C2-C18)alkenyl, (C8-C26)aralkenyl, (C2-C18)- alkynyl, (C8-C26)aralkynyl and heterocyclic, any of which may be optionally substituted as defined below,
and R80 is selected from the group consisting of R81 as previously defined and a solubilising and/or protecting group Px which is labile in vivo, then at least one of the following applies:
(i) R50 is a group R53, wherein R53 is selected from the group consisting of
C(D*)OR21*, C(D*)NR21*R22*, C(D*)SR21*, C(D*)R55, CF3, R55 and a solubilising group Px which is labile in vivo, wherein
D* has the meaning of D as previously defined,
R21* and R22* have the meaning of R2 1 and R22 respectively, as previously defined,
and wherein R55 is selected from the group consisting of optionally substituted (C1-C18)alkyl(C6-C24)aryl, optionally substimted
(C2-C18)alkenyl(C6-C24)aryl, optionally substimted (C2-C18)- alkynyl(C6-C24)aryl, optionally substimted (C3-C18)cycloalkyl(C2.C18)alkenyl, optionally substimted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substimted (C3-C18)cycloalkyl- (C6-C24)aryl, optionally substimted acyl(C6-C24)aryl, optionally substimted heterocyclic(C1-C18)alkyl, optionally substimted heterocyclic(C2-C18)alkenyl, optionally substituted heterocyclic- (C2-C18)alkynyl and optionally substituted heterocyclic(C2-C18)- (C6-C24)aryl,
and n', m', R1*, R10, A', A'*, R51 and R2* are as previously defined,
(ii) one of R2* and R51 is a group R54, wherein R54 is selected from the group consisting of R55*, C(D*)NR21*R22*, C(D*)OR55*, C(D*)R55*,
C(D*)SR21*, CF3, S(O)zOR120, S(O)zNR120R101. and a solubilising group Px which is labile in vivo, wherein z is 1 or 2 and R120 and R121 are as previously defined or R120 and R121 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined below, and wherein R21* and R22* have the meaning of R21 and R22 respectively, as previously defined, and R55* has the meaning of R55, as previously defined,
and n', m', R1*, R10, A', A'*, R50 and the other of R2* and R51 are as previously defined,
(iii) at least one A' or A'* is selected from the group consisting of CR112R13,
CR12R113, CR112R13* and CR12*R113, wherein R112 and R113 are independently selected from the group consisting of R55 as previously defined, C(D)OR21*, C(D)SR21*, C(D)NR21*R22*, F, Cl, Br and I, wherein R21* and R22* have the meaning of R21 and R22 respectively, as previously defined,
and D, n', m', R1*, R2*, R10, R1 1, R12, R12*, R13, R13*, R50 and R51 are as previously defined,
(iv) R1* is selected from the group consisting of optionally substituted
(C2-C18)alkenyl, optionally substimted (C2-C18)alkynyl, optionally substimted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substimted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substimted (C6-C24)aryl- (C2-C18)alkenyl, optionally substimted (C6-C24)aryl(C2-C18)alkynyl, optionally substimted (C2-C18)acyl, wherein the optional substituent is other than amino, optionally substimted (C6_C24)aryl(C2-C18)acyl, optionally substimted heterocyclic(C1-C18)alkyl, optionally substimted heterocyclic(C2-C18)alkenyl, optionally substimted heterocyclic(C2-C18)alkynyl, C(O)OR90, C(O)NR91R92, CF3,
S(O)zOR120, S(O)zNR120R121 and a solubilising group Px which is labile in vivo,
wherein z is 1 or 2 and R120 and R121 are as previously defined, wherein R90 is selected from the group consisting of (C3-C18)cycloalkyl,
(C3-C18)cycloalkyl(C1-C18)alkyl, heterocyclic, (C1-C18)alkyl- heterocyclic, (C6-C24)aryl, (C6-C24)aryl(C1-C18)alkyl and
(C6-C24)aryl(C 1 -C 18)alkylheterocyclic ,
and wherein R91 and R92 are independently selected from the group consisting of optionally substituted (C2-C18)alkenyl, optionally substituted (C2-C18)alkynyl, optionally substimted
(C3-C18)cycloalkyl, optionally substimted (C3-C1g)cycloalkyl(C1-C18)alkyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substituted (C3-C18)cycloalkyl¬
(C2-C18)alkynyl, optionally substituted (C6-C24)aryl(C2-C18)alkenyl, optionally substituted (C6-C24)aryl(C2-C18)alkynyl, optionally substituted (C2-C18)acyl, optionally substituted (C6-C24)aryl(C2-C18)acyl, optionally substituted heterocyclic, optionally substituted heterocyclic(C1-C18)alkyl, optionally substimted heterocyclic(C2-C18)alkenyl, and optionally substituted heterocyclic(C2-C18)alkynyl, or R91 and R62 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
and m' , n', A', A'*, R2*, R50, R51 and R10 are as previously defined,
(v) a group selected from R1, R1*, R2, R2*, R9, R11, R12, R50 and R51, taken together with another group selected from R1, R1*, R2, R2*, R9*, R10, R11, R12, R50 and R51 is selected from the group consisting of -C(O)- and optionally substimted methylene; (b) when W is R1*X* wherein X* is NR10, and V' is Y* wherein Y* is
Figure imgf000021_0001
, and B' is selected from -CH(OH)- and -C(O)- then at least one of the following also applies when one of the conditions (i) to (iv) defined above in (a) applies:
(vi) n' > 1,
(vii) n' = 0,
(viii) m' > 1,
(ix) m' = 0,
(x) R50 and R51 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
(xi) R50 is a group R56, wherein R56 is selected from the group consisting of C(D*)OR21*, C(D*)NR21*R22*, C(D*)SR21*, C(D*)R55 and a solubilising and/or protecting group Px which is labile in vivo, wherein R21* and R22* are as previously defined, and (xii) n' = m' = 1 and A'* is other than -CH2-, and (c) when B' is selected from
Figure imgf000022_0002
Figure imgf000022_0003
Figure imgf000022_0001
Figure imgf000022_0004
Figure imgf000022_0005
, , , ,
and
Figure imgf000022_0006
, wherein R14, R14* and R17 are as previously defined,
then at least one group selected from R2 or R2*, R11, R12, R50 and R51 together with another group selected from Rμ or R1*, R10, R11 and R12 forms a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, said ring being substimted with at least one polar group selected from =O,
=S, OH, SH, NHR10* and C(O)OH, wherein R10* has the meaning of R10 as previously defined, said polar group being sterically capable of being located within the compound of formula (I) not more than 5 Ångstrom units from the
P, O, S, N or C atom of group B,
provided that when W' is R1*X* and X* is NH and V' is Y* wherein Y* is
Figure imgf000022_0007
wherein R1* is other than H and R71 and R72 are independently selected from the group consisting of H, (C1-C6)alkyl, optionally substimted phenyl, optionally substimted naphthyl, optionally substimted phenyl(C1-C2)alkyl and optionally substimted naphthyl¬
(C1-C2)alkyl, and when
(a) B' is -CH(OH)- and (A')n is -CH(R73)- wherein R73 is selected from the group consisting of (C1-C6)alkyl optionally substimted with 1-5 fluorine atoms, (C3-C6)alkenyl, (C1-C6)alkoxy-CH2-, (CH2)pphenyl, (CH2)pnaphthyl, (CH2)p.
(C5-C6)cycloalkyl and (CH2)pindolyl, wherein said (CH2)nphenyl, (CH2)nnaphthyl, (CH2)n(C5-C6)cycloalkyl and (CH2)nindolyl are optionally substimted with nitro, halogen, (C1-C4)alkyl, (C1-C4)alkoxy or (C1-C4)alkylthio and wherein p is 0, 1 or 2, then (A'*)m' is other than wherein R74 has the meaning of R73 as previously defined, and
Figure imgf000022_0008
when (b) B' is wherein R74 has the meaning of R73 as previously defined and
Figure imgf000023_0003
(A')n' is wherein R73 is as previously defined, then (A'*)m' is
Figure imgf000023_0002
other than -C(O)-, and when
(c) B' is -C(O)- and (A')n' is wherein R73 is as previously
Figure imgf000023_0001
defined, then m' is other than 0.
As used herein, the term "(C1-C18)alkyl" includes within its meaning straight and branched chain alkyl groups having from 1 to 18 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1- or 2-pentylheptyl, tridecyl, tetradecyl, hexadecyl, octadecyl and the like.
Typically an alkyl group is (Ca-Cb)alkyl, in which a is selected from a value presented in the column headed "a" in Table A below at one of entries 1-17, and b has one of the values presented in the column headed "b" at that entry.
Figure imgf000023_0004
Figure imgf000024_0001
As used herein, the term "(C2-C18)alkenyl" includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched. Examples of such alkenyl groups are vinyl, allyl, 1-methylvinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 2-methylpentenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1,3-octadienyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1-undecenyl, oleyl, linoleyl and linolenyl.
Typically an alkenyl group is (Ca-Cb)alkenyl, in which a is selected from a value presented in the column headed "a" in Table A above at one of entries 2-17, and b has one of the values presented in the column headed "b" at that entry.
As used herein, the term "(C2-C18)alkynyl" includes within its meamng mono-, di- and poly-acetylenically unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-1-butynyl, n-hexynyl, methyl-pentynyl and
(C7-C12)alkynyl.
Typically an alkynyl group is (Ca-Cb)alkynyl, in which a is selected from a value presented in the column headed "a" in Table A above at one of entries 2-17, and b has one of the values presented in the column headed "b" at that entry.
As used herein, the term "(C3-C18)cycloalkyl" refers to otionally unsamrated mono-, di- or polycyclic alkyl groups having from 3 to 18 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, (C9-C12)cycloalkynyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]heptadienyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[3.3.1]nonyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.0]octyl, bicyclo[3.3.0]octenyl, bicyclo[3.3.1]nonyl, bicyclo[4.4.0]decyl, adamantyl, tricyclo[5.2.1.02,6]decyl and the like.
Typically a cycloalkyl group is (Ca-Cb)cycloalkyl, in which a is selected from a value presented in the column headed "a" in Table A above at one of entries 3-17, and b has one of the values presented in the column headed "b" at that entry.
As used herein, the term "(C3-C18)cycloalkyl(C1-C18)alkyl" refers to a (C1-C18)alkyl group as defined above, substimted with a (C3-C18)cycloalkyl group as defined above. Examples of cycloalkylalkyl groups include cycloalkyl-loweralkyl groups, such as cycloalkylmethyl, cycloalkylethyl, cycloalkylpropyl, cycloalkylbutyl, cycloalkylisopropyl, cycloalkylisobutyl, cycloalkylpentyl and cycloalkylhexyl, wherein the cycloalkyl is as exemplified in the preceding paragraph.
As used herein, the term "(C3-C18)cycloalkyl(C2-C18)alkenyl" refers to a
(C2-C18)alkenyl group as defined above, substimted with a (C3-C18)cycloalkyl group as defined above. Examples of cycloalkylalkenyl groups include cycloalkyl-loweralkenyl groups, such as cycloalkylethenyl, cycloalkylpropenyl, cycloalkylbutenyl, cycloalkylisobutenyl, cycloalkylpentenyl and cycloalkylhexenyl, wherein the cycloalkyl is as exemplified above under "(C3-C18)cycloalkyl".
As used herein, the term "(C3-C18)cycloalkyl(C2-C18)alkynyl" refers to a (C2-C18)alkynyl group as defined above, substituted with a (C3-C18)cycloalkyl group as defined above. Examples of cycloalkylalkynyl groups include cycloalkyl-loweralkynyl groups, such as cycloalkylethynyl, cycloalkylpropynyl, cycloalkylbutynyl, cycloalkylpentynyl and cycloalkylhexynyl, wherein the cycloalkyl is as exemplified above under " (C3-C18)cycloalkyl".
As used herein, the term "(C6-C24)aryl" refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons having from 6 to 24 carbon atoms. Examples of such groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, acenaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, indanyl, azulenyl, chrysenyl and the like. In all cases, any available position of the fused or conjugated bicyclic system can be used for attachment to the remainder of the molecule of formula
(I).
Typically an aryl group is (Ca-Cb)aryl, in which a is selected from a value presented in the column headed "a" in Table B below at one of entries 1-18, and b has one of the values presented in the column headed "b" at that entry.
Figure imgf000025_0001
Figure imgf000026_0001
As used herein, the term "(C6-C24)aryl(C1-C18)alkyl" refers to a (C1-C18)alkyl group substimted with one or more (C6-C24)aryl groups as previously defined. Examples of such groups are aryl-loweralkyl groups such as arylmethyl, arylethyl, arylisopropyl, arylpropyl, arylbutyl, arylisobutyl, arylpentyl and arylhexyl, wherein the aryl is as exemplified in the preceding paragraph, such as benzyl, diphenylmethyl, 2-phenylethyl, 1-phenylethyl, naphthylmethyl, 3-phenylpropyl, triphenylmethyl, 1,3-diphenylpropyl, 2- or 3-β-naphthylpropyl, 2-benzyl-propyl and the like.
As used herein, the term "(C7-C25)aralkyl" refers to an alkyl group substimted with an aryl group, wherein the total number of carbon atoms in the aryl-substimted alkyl group is from 7 to 25. Optional substituents for (C7-C25)aralkyl are as defined below with respect to (C6-C24)aryl(C1-C18)alkyl.
As used herein, the term "(C6-C24)aryl(C1-C18)alkenyr' refers to a (C1-C18)alkenyl group substituted with one or more (C6-C24)aryl groups as previously defined. Examples of such groups are aryl-loweralkenyl groups such as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and arylhexenyl, wherein the aryl is as exemplified above under "(C6-C24)aryl" such as styryl, cinnamyl, 2-naphthylethenyl, l-phenyl-2-methyl-l-propenyl, 2-phenyl-2-butenyl and the like.
As used herein, the term "(C8-C26)aralkenyl" refers to an alkenyl group substimted with an aryl group, wherein the total number of carbon atoms in the arylsubstimted alkenyl group is from 8 to 26. Optional substituents for (C8-C26)aralkenyl are as defined below with respect to (C6-C24)aryl(C2-C18)alkenyl.
As used herein, the term "(C6-C24)aryl(C1-C18)alkynyl" refers to a (C1-C18)alkynyl group substimted with one or more (C6-C24)aryl groups as previously defined. Examples of such groups are aryl-loweralkenyl groups such as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and arylhexenyl, wherein the aryl is as exemplified above under "(C6-C24)aryl" such as phenylethynyl and the like.
As used herein, the term "(C8-C26)aralkynyl" refers to an alkynyl group substimted with an aryl group, wherein the total number of carbon atoms in the arylsubstimted alkynyl group is from 8 to 26. Optional substituents for (C8-C26)aralkynyl are as defined below with respect to (C6-C24)aryl(C2-C18)alkynyl.
As used herein, the term "(C1-C18)acyl" refers to a group R300C(O)- or R300C(S)-, wherein R300 is selected from the group consisting of hydrogen, (C1-C18)alkyl, (C2-C18)alkenyl, (C2-C18)alkynyl, (C3-C18)cycloalkyl (C3-C18)cycloalkyl(C1-C18)alkyl, (C3-C18)cycloalkyl(C2-C18)alkenyl, (C3-C18)cycloalkyl(C2-C18)alkynyl, (C6-C24)aryl, (C6-C24)aryl(C1-C18)alkyl, (C6-C24)aryl(C2-C18)alkenyl, (C6-C24)aryl(C2-C18)alkynyl, heterocyclic, heterocyclic(C1-C18)alkyl, heterocyclic(C2-C18)alkenyl, and heterocyclic(C2-C18)alkynyl.
Typically an acyl group is (Ca-Cb)acyl, in which a is selected from a value presented in the column headed "a" in Table A above at one of entries 1-17, and b has one of the values presented in the column headed "b" at that entry.
Examples of acyl groups include loweralkylcarbonyl such as formyl, acetyl, propionyl, butyryl; loweralkenylcarbonyl such as pivaloyl, acryloyl, vinylacetyl, crotonoyl, 3-pentenoyl, 4-pentenoyl; and loweralkynylcarbonyl such as propioloyl, 2-butynoyl and 3-butynoyl, any of which may be substimted with cycloalkyl, aryl or heterocyclic as exemplified herein, as, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 1-cyclopentenylcarbonyl, cyclopentylacetyl, cyclohexylcarbonyl, 1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl, cyclohexylacetyl, cyclohexenylacetyl, 1 ,4cyclohexadienylacetyl, bicyclo[2.2.1]hept-2-ylcarbonyl, bicyclo[2.2.1]heptylacetyl, bicyclo[2.2.1]hepten-2-ylcarbonyl, bicyclo[2.2.2]oct-2-ylcarbonyl, bicyclo[2.2.2]octylacetyl, bicyclo[2.2.2]octyl-3-propionyl, bicyclo[2.2.2]octen-2-ylcarbonyl, bicyclo[3.3.1]non-9-ylcarbonyl, bicyclo[3.3.1]non-9-ylacetyl, bicyclononyl-3propionyl, bicyclo[4.4.0]dec-2-ylcarbonyl, bicyclo[4.4.0]dec-2-ylacetyl, 1-adamantylcarbonyl, 2-adamantylcarbonyl, 1-adamantylacetyl, 2-adamantylacetyl, tricyclo[5.2.1.02,6]dec-8-ylacetyl, benzoyl, phenylacetyl, diphenylacetyl, triphenylacetyl, 3-phenylpropionyl, dibenzylacetyl, α-naphthoyl, β-naphthoyl, α-naphthylacetyl, β-naphthylacetyl, indenylcarbonyl, indanylcarbonyl, phenanthrenylcarbonyl, 9-fluorenylcarbonyl, pyrrolylcarbonyl, pyrrolylacetyl, furylcarbonyl, furylacetyl, thienylcarbonyl, thienylacetyl, pyrazinylcarbonyl, pyrazinylacetyl, pyrrolidinylcarbonyl, pyrrolidinylacetyl, pyridylcarbonyl, pyridylacetyl, pyrimidinylcarbonyl, pyrimidinylacetyl, piperidylcarbonyl, piper idylacetyl, piperazinylcarbonyl, piperazinylacetyl, morpholinylcarbonyl, morpholinylacetyl, thiomorpholinylcarbonyl, thiomorpholinylacetyl, indolylcarbonyl, indolylacetyl, quinolylcarbonyl, quinolylacetyl, isoquinolylcarbonyl, isoquinolylacetyl, quinoxalinylcarbonyl, benzofuranylcarbonyl, benzofuranylacetyl, indolinylcarbonyl, indolinylacetyl, 1,2,3,4-tetrahydroquinolylcarbonyl, 1,2,3,4-tetrahydroquinolylacetyl, 1,2,3,4-tetrahydroisoquinolylcarbonyl, 1,2,3,4-tetrahydroisoquinolylacetyl, cyclohexylacryloyl, cinnamoyl, styrylacetyl and phenylpropioloyl.
As used herein, the term "heterocyclic" refers to any samrated or unsaturated 3- to 16-membered monocyclic, bicyclic or poly cyclic ring containing one or more heteroatom independently selected from oxygen, nitrogen and sulphur. The term "heterocyclic" includes any group in which a heterocyclic ring is fused to one or more benzene, naphthalene or cycloalkane rings. Sulfur-containing heterocyclics may be substimted at sulfur with one or two oxygen atoms. Examples of heterocyclics are pyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridazinyl, perhydropyridazinyl, pyrazolyl, pyrazoldinyl, 2,3,5,6-tetrahydropyrazinyl, phthalazinyl, 1,2,3,4-tetrahydrophthalazinyl, perhydrophthalazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl, piperidyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolidino, oxazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolinyl, benzothienyl, benzisoxazolyl, benzoisothiazolyl, benzothiadiazolyl, tetrazolyl, triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl, 1,4-thioxanyl, 1,3-thioxanyl, azanorbornyl, isoquinuclidinyl, pyranyl, furazanyl, azepinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, quinoxalinyl, cinnolyl, 1,2,3,4-tetrahydrocinnolinyl, pteridinyl, naphthyridinyl, 4H-quinolizinyl, benz[e] indolyl, benzoxazinyl, benzoxadiazolyl, benzothiazinyl, benzotriazolyl, carbazolyl, β-carbolinyl, 1,2,3,4,5,6-hexahydro-β-carbolinyl, phenanthridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthenyl, thiatriazolyl, oxadiazolyl, thiadiazolyl, chromanyl, thiachromanyl, isochromanyl, chromenyl, cyclohexa[b]pyrrolyl, cyclohepta[b]pyrrolyl, cyclohexa[d]pyrazolyl. cyclohexa[b]pyridyl, cyclohexa[b]pyrazinyl, cyclohexa[b]pyrimidinyl, cyclohexa[b]-l,4-oxazinyl, cyclohexa[b]1,4-thiazinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperazinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, indolinyl, S,S-dioxo-l,2,3-benzothiadiazolyl, S,S-dioxo-l,2thioxanyl, S,S-dioxo-1,4-thioxanyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, hexahydroquinolyl. hexahydroisoquinolyl, 1,2,3,4-tetrahydro-3,1-benzodiazinyl, 3,4-dihydro-3H-4, 1-benzoxazinyl, 3,4-dihydro-3H-4,1-benzothiazinyl, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl and 5,6-dihydrophenanthridinyl and the like.
Configurations which result in unstable heterocyclics are not included within the scope of the definition of "heterocyclic" or "samrated or unsamrated cyclic, bicyclic or fused ring system".
As used herein, the term "heterocyclic(C1-C18)alkyl" refers to a (C1-C18)alkyl group as previously defined, which is substimted with a heterocyclic group as previously defined. Examples of such groups are heterocyclic-loweralkyl groups such as hetero- cyclicmethyl, heterocyclicethyl, heterocyclicisopropyl, heterocyclicpropyl, heterocyclicbutyl, heterocyclicisobutyl, heterocyclicpentyl and heterocyclichexyl, wherein the heterocyclic is as exemplified in the preceding paragraph.
As used herein, the term "heterocyclic(C1-C18)alkenyl" refers to a (C1-C18)alkenyl group as previously defined, which is substimted with a heterocyclic group as previously defined. Examples of such groups are heterocyclic-loweralkenyl groups such as heterocyclicethenyl, heterocyclicpropenyl, heterocyclicbutenyl, heterocyclicisobutenyl, heterocyclicpentenyl and heterocyclichexenyl, wherein the heterocyclic is as exemplified above under "heterocyclic".
As used herein, the term "heterocyclic(C1-C18)alkynyl" refers to a
(C1-C18)alkynyl group as previously defmed, which is substituted with a heterocyclic group as previously defmed.
As used herein, the term "alkylidene" refers to divalent radicals derived from alkyl groups. Examples of such radicals are -CH2-, -CH2CH2-, -CH=CH-, -CH2CH2CH2-, -C(=CH2)CH2-, -CH2CH=CH-, -(CH2)4-, -CH2CH2CH=CH-, -CH2CH=CHCH2- and -(CH2)r- where r is 5-12. The term also refers to such radicals in which one or more of the bonds of the radical from part of a cyclic system, and to such radicals wherein one or more carbon atoms is replaced by O, S or NH. Examples of such radicals are groups of the structure
Figure imgf000029_0001
Figure imgf000030_0001
and similar groups, including those shown above wherein any N or O atom is replaced by S.
As used herein the term "samrated or unsaturated cyclic, bicyclic or fused ring system" refers to a stable cyclic system of up to 16 carbon atoms, wherein said ring system may contain: for 3- and 4-membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 11-membered rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16-membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur; which ring system may be substimted with one or more substituents independently selected from: R150 and a group T, where R150 has the meaning of R20 as previously defmed, and where T is selected from the group consisting of -F, -Cl, -Br, -I, -CF3, -CN, -NCO, -NCS, -OCN, -SCN, -N3, -OR' , -NR'R" , -NR'C(O)R", -NR'C(O)OR", -NR'C(O)NR''R' ", -NO2, -SR', -S(O)R', -S(O)2R', -S(O)OR' , -S(O)2OR', -S(O)NR'R", -S(O)2NR'R", =O, =S, =N2, =NOH, =NOR' , -NR'OR', -CHO, -OC(O)R', -OC(O)OR', -OC(O)NR'R", -C(O)R', -C(O)OR', -C(O)NR'R", -OC(S)R' , -OC(S)OR', -OC(S)NR'R", -C(S)R', -C(S)OR', -C(S)NR'R" , -SC(O)R', -SC(O)OR', -SC(O)NR'R", -C(O)SR', -SC(S)R', -SC(S)OR', -SC(S)NR'R", -C(S)SR', -C(=NR')OR", -C(=NR')SR", -C(=NR,)NR"R"', -OS(O)R', -OS(O)2R' , -OS(O)OR', -OS(O)2OR', -OS(O)NR'R", -OS(O)2NR'R'', NR'S(O)2NR''R' " , -NR'S(O)2R", -NHC(=NH)NR' , -C(=NH)NR', -P(O)(OR')R", -P(O)(SR')R", -P(O)(OR')OR", -P(O)(OR,)NR"R'' ', -P(O)R'R", -OP(O)(OR')R", -OP(O)(OR')OR" , -OP(O)(SR')OR", -OP^^R^NR' 'R' '', -OP(O)R'R'' , and -B(OR')(OR"), wherein R', R" and R' " are independently selected from the group consisting of hydrogen, (C1-C18)alkyl, typically (C1-C12)alkyl; (C3-C18)cycloalkyl, typically (C3-C12)cycloalkyl; (C3-C18)cycloalkyl(C1-C18)alkyl, typically (C3-C12)cycloalkyl(C1-C6)alkyl; (C6-C24)aryl, typically (C6-C16)aryl; (C6-C24)aryl(C1-C18)alkyl, typically (C6-C10)aryl(C1-C6)alkyl; (C2-C18)alkenyl, typically (C2-C12)alkenyl; (C6-C24)aryl(C2-C!8)alkenyl, typically (C6-C10)aryl(C2-C6)alkenyl; (C2-C18)alkynyl, typically (C2-C12)alkynyl; (C6-C24)aryl(C2-C18)aralkynyl, typically (C6-C10)aryl(C1-C6)alkynyl, heterocyclic, heterocyclic(C1-C18)alkyl, typically heterocyclic(C1-C12)alkyl, heterocyclic(C2-C18)alkenyl, typically heterocyclic(C2-C12)alkenyl and heterocyclic(C2-C18)alkynyl, typically heterocyclic(C2-C12)alkynyl, and wherein R', R" and R' " may be optionally substimted with up to six groups independently selected from hydroxy, (C1-C6)alkoxy, (C1-C6)aryloxy, (C1-C6)thioalkoxy, (C1-C6)thioaryloxy, (C1-C6)alkoxy(C1-C6)alkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, fluoro, chloro, bromo, iodo, carboxy, (C1-Cg)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl and di(C1-C6)alkylaminocarbonyl. Examples of samrated or unsamrated cyclic, bicyclic or fused ring systems are the heterocyclic and cyclic alkylidene groups exemplified above.
As used herein, the term "optionally substimted (C1-C18)alkyl" refers to a (C1-C18)alkyl group as defined above wherein one or more hydrogen atoms are replaced by one or more substitutents T as previously defined.
Examples of substimted (C1-C18)alkyl groups include hydroxy-loweralkyl such as hydroxymethyl, hydroxyethyl and 3-hydroxypropyl; loweralkoxy-loweralkyl such as methoxy methyl, 2-methoxyethyl, 2,2-dimethoxyethyl and 3-methoxypropyl; aryloxyloweralkyl such as phenoxymethyl, phenoxy ethyl, α-naphthyloxymethyl and β-naphthyloxyethyl; arylloweralkoxy-loweralkyl such as benzyloxymethyl, benzyloxyethyl and 3-benzyloxypropyl; halo-loweralkyl such as chloromethyl, trifluoromethyl, 2-fluoro-, 2-chloro-, 2-bromo- or 2-iodo-ethyl, 2,2,2-trifluoro-ethyl, 2,2,2-trichloro-ethyl, 3-chloropropyl and 3-bromopropyl; amino-loweralkyl such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 5-aminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl and 3-phenyl- aminopropyl; carboxy-loweralkyl such as carboxymethyl, carboxyethyl and 3-carboxypropyl; acylloweralkyl such as acylmethyl, acylethyl, acylpropyl, acylisopropyl, acylbutyl, acylisobutyl, acylpentyl and acylhexyl wherein the acyl is as exemplified above under "(C1-C18)acyl"; acyloxy-loweralkyl such as acetoxymethyl, acetoxyethyl, 2-acetoxypropyl, 3-acetoxypropyl, propionyloxyethyl and 3-propionyloxypropyl; loweralkylcarbonylamino-loweralkyl such as acetylaminomethyl, acetylaminoethyl, 2-acetylaminopropyl, propionylaminomethyl and propionylaminoethyl; loweralkylaminocarbonylamino-loweralkyl, such as dimethylaminocarbonylaminoethyl; sulfonyl-loweralkyl such as methylsulfonyl-methyl, ethylsulfonyl-methyl, tert-butylsulfonyl-methyl, phenylsulfonylmethyl, phenylsulfonylethyl, 4-toluenesulfonylethyl and 4-toluenesulfonylmethyl; cyano-loweralkyl such as cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 2-cyanobutyl, 3-cyanobutyl and 4-cyanobutyl; oxo-loweralkyl such as 2-oxo-propyl, 2-oxo-butyl, 3-oxo-butyl, 2-, 3- or 4-oxo-pentyl and 2,4-dioxo-pentyl; and loweralkyl groups substimted with two or more than different substitutents as exemplified above.
As used herein, the term "optionally substimted (C1-C18)alkenyl" refers to a (C1-C18)alkenyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defmed.
As used herein, the term "optionally substimted (C1-C18)alkynyl" refers to a (C1-C18)alkynyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defined.
As used herein, the term "optionally substimted (C3-C24)cycloalkyl" refers to a (C3-C24)cycloalkyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents independently selected from RIV and T as previously defined, wherein RIV is selected from (C1-C1g)alkyl, (C2-C18)alkenyl, (C2-C18)alkynyl, (C3-C18)cycloalkyl, (C3-C18)cycloalkyl(C1-C18)alkyl, (C3-C18)cycloalkyl(C2-C18)alkenyl, (C3-C18)cycloalkyl(C2-C18)alkynyl, (C2-C18)acyl,
(C6-C24)aryl(C2-C18)acyl, heterocyclic, heterocyclic(C1-C18)alkyl, heterocyclic(C2-C18)alkenyl, and heterocyclic(C2-C18)alkynyl, and wherein RIV may be substituted with up to six groups independently selected from hydroxy, amino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, fluoro, chloro, bromo, iodo, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl and di(C1-C6)alkylaminocarbonyl.
As used herein, the term "optionally substimted (C3-C24)cycloalkyl(C1-C18)alkenyl" refers to a (C3-C24)cycloalkyl(C1-C18)alkenyl group as defined above which are substimted in the cycloalkyl group by a substituent or substitutents independently selected from the substituents defined above for (C3-C24)cycloalkyl, and/or substimted in the alkenyl group by one or more substituents T as previously defined. As used herein, the term "optionally substimted (C3-C24)cycloalkyl(C1-C18)alkynyl" refers to a (C3-C24)cycloalkyl(C1-C18)alkynyl group as defined above which are substituted in the cycloalkyl group by a substituent or substitutents independently selected from the substituents defined above for (C3-C24)cycloalkyl, and/or substituted in the alkynyl group by one or more substituents T as previously defined.
As used herein, the term "optionally substimted (Cg-C^aryl" refers to a (C6-C24)aryl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents independently selected from Rv and T*, wherein T* is selected from the group consisting of -F, -Cl, -Br, -I, -CF3, -CN, -NCO, -NCS, -OCN, -SCN, -N3, -OR', -NR'R", -NR'C(O)R", -NR'C(O)OR", -NR,C(O)NR"R' ' ' , -NO2, -SR' , -S(O)R' , -S(O)2R', -S(O)OR', -S(O)2OR', -S(O)NR'R", -S(O)2NR'R", -NR' OR', -CHO, -OC(O)R' , -OC(O)OR', -OC(O)NR'R", -C(O)R' , -C(O)OR', -C(O)NR'R", -OC(S)R', -OC(S)OR', -OC(S)NR'R", -C(S)R ', -C(S)OR' , -C(S)NR'R", -SC(O)R' , -SC(O)OR' , -SC(O)NR'R", -C(O)SR', -SC(S)R', -SC(S)OR' , -SC(S)NR'R", -C(S)SR', -C(=NR')OR", -C(=NR')SR", -C(=NR')NR"R" ', -OS(O)R' , -OS(O)2R', -OS(O)OR', -OS(O)2OR', -OS(O)NR'R", -OS(O)2NR'R", NR'S(O)2NR"R'" , NR'S(O)2R", -NHC(=NH)NR', -C(=NH)NR', -OP(O)(OR')R", -OP(O)(OR')OR" , OP(O)(SR')OR", -OP(O)(OR,)NR"R' ' ', -OP(O)R'R", and -B(OR')(OR"), wherein R', R" and R" ' are as defined above with respect to the substituent T; and wherein Rv is selected from (C1-C18)alkyl, (C2-C18)alkenyl, (C2-C18)alkynyl, (C3-C18)cycloalkyl, (C3-C18)cycloalkyl(C1-C18)alkyl, (C3-C18)cycloalkyl(C2-C18)alkenyl, (C3-C18)cycloalkyl(C2-C18)alkynyl, (C2-C18)acyl, (C6-C24)aryl(C2-C18)acyl, heterocyclic, heterocyclic(C1-C18)alkyl, heterocyclic(C2-C1g)alkenyl, and heterocyclic(C2-C18)alkynyl, and wherein Rv may be substimted with up to six groups independently selected from hydroxy, amino, (C1-C6)alkoxy, (C1-C6)aryloxy, (C1-C6)thioalkoxy, (C1-C6)thioaryloxy, (C1-C6)alkoxy(C1-C6)alkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, fluoro, chloro, bromo, iodo, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl and di(C1-C6)alkylaminocarbonyl. The term "optionally substimted (C6-C24)aryl" includes mono-, di- and poly substimted (C6-C24)aryl groups.
Examples of substimted aryl groups are loweralkyl-aryl, loweralkenyl-aryl, arylloweralkyl-arylloweralkylcarbonyl-aryl, heterocyclic-aryl and heterocyclicloweralkyl-aryl wherein the aryl group is as exemplified above; halo-aryl such as 4-chlorophenyl, 2,4-dichlorophenyl, 1-chloro-2-naphthyl and 4-chloro-1-naphthyl; hydroxy-aryl such as 2-hydroxyphenyl, 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 2-hydroxy-8-naphthyl, 3,4,5-trihydroxyphenyl and 2,4,5-trihydroxyphenyl; loweralkoxyaryl such as 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl and 1-methoxy-2-naphthyl; carboxyaryl such as 2-carboxy-phenyl, 2-carboxy-1-naphthyl, 1-carboxy-2-naphthyl and 9-carboxy-2-anthracyl; acylaryl, wherein the acyl group is as exemplifed above under "(C1-C18) acyl", such as 4-formylphenyl, 4-acetylphenyl, 2-benzoylphenyl, 2-methoxycarbonyl-phenyl , 2-ethoxycarbonyl- 1 -naphthyl, 1-methoxycarbonyl-2-naphthyl, 9-methoxycarbonyl-2-anthracyl, 2-carbamoyl-phenyl, 2-carbamoyl-1-naphthyl,
1-carbamoyl-2-naphthyl, 4-dimethylaminocarbonyl-phenyl, 4-morpholinocarbonylphenyl, 4-(2-pyridylmethoxy)carbonyl-phenyl and 4-benzyloxycarbonyl-phenyl; nitro-aryl such as 4-nitrophenyl and 2,4-dinitrophenyl; amino- or (substituted amino)-aryl such as 4-aminophenyl, 2,4-diaminophenyl, 4-dimethylaminophenyl, 4-anilinophenyl, 2-(2,6-dichloroanilino)-phenyl, 2,4-di-(benzyloxycarbonylamino)-phenyl and 4-(2-quinolinecarbonylamino)-phenyl; and cyano-aryl such as 4-cyanophenyl, as well as aryl groups substimted with two or more of the substituents exemplified above.
As used herein, the term "optionally substituted (C6-C24)aryl(C1-C18)alkyl" refers to a (C6-C24)aryl(C1-C18)alkyl group as previously defined substituted in the aryl group with one or more substimtents defined above for (C6-C24)aryl and/or substimted in the alkyl group with one or more substimtents defined above for (C1-C18)alkyl. Examples of such groups are (substimted aryl)-lower-alkyl such as (substituted aryl)methyl, (substituted aryl)ethyl, (substituted aryl)propyl, (substimted aryl)iso-propyl, (substimted aryl)butyl, (substimted aryl)pentyl and (substimted aryl)hexyl, aryl(substituted loweralkyl) such as phenyl(substituted loweralkyl), naphthyl(substituted loweralkyl), biphenyl(substimted loweralkyl), tetrahydronaphthyl (substimted loweralkyl), indenyl(substimted loweralkyl) and indanyl (substimted loweralkyl), and (substimted aryl)(substituted loweralkyl), wherein in each case substimted aryl is as exemplified above with respect to "optionally substimted (C6-C24)aryl" and (substimted loweralkyl) is as exemplified above with respect to "optionally substimted (C1-C18)alkyl".
As used herein, the term "optionally substimted (C6-C24)aryl(C1-C18)alkenyl" refers to a (C6-C24)aryl(C1-C18)alkenyl group as previously defmed substimted in the aryl group with one or more substimtents defmed above for (C6-C24)aryl and/or substimted in the alkenyl group with one or more substimtents defined above for (C1-C18)alkyl.
As used herein, the term "optionally substimted (C6-C24)aryl(C1-C18)alkynyl" refers to a (C6-C24)aryl(C1-C18)alkynyl group as previously defined substimted in the aryl group with one or more substimtents defined above for (C6-C24)aryl and/or substimted in the alkynyl group with one or more substimtents defined above for (C1-C18)alkyl.
As used herein, the term "optionally substituted (C1-C18)acyl" refers to a (C1-C18)acyl group as previously defmed which may be substimted with one or more groups selected from the substituents defined for (C1-C18)alkyl, and includes within its meaning an acyl residue of a namrally occurring or synthetic amino acid or azaamino acid, or an acyl residue of a peptide chain containing 2-4 namrally occurring or synthetic amino acids and/or azaamino acids.
Examples of substimted acyl groups include acyl residues of any of the namrally occurring or synthetic amino acids exemplified herein, hydroxy loweralkanoyl, loweralkoxyloweralkanoyl, acetylloweralkanoyl, cyanoloweralkanoyl, carboxy loweralkanoyl, hydroxycarboxy loweralkanoyl, fluoroloweralkanoyl, chloroloweralkanoyl, bromoloweralkanoyl, thioloweralkanoyl, loweralkanethioloweralkanoyl, aminoloweralkanoyl, loweralkylaminoloweralkanoyl, di-(loweralkylamino)loweralkanoyl, carbamoylloweralkanoyl, loweralkoxy carbonyl, carbamoyl, loweralkylaminocarbonyl and di-(loweralkylamino)carbonyl, where loweralkanoyl is an alkanoyl group of from 1 to 6 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl, and where loweralkyl signifies a (C1-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl and hexyl.
As used herein, the term "optionally substimted heterocyclic" refers to a heterocyclic group as previosly defined wherein one or more hydrogen atoms may be replaced with a group selected from the substitutents defmed above with regard to optionally substituted (C6-C24)aryl. Examples of substited heterocyclic groups include loweralkylheterocyclic, arylheterocyclic, aryloxyheterocyclic, loweralkoxyheterocyclic, oxo-heterocyclic, hydroxyheterocyclic, loweralkoxycarbonylheterocyclic and loweralkanoy lheterocyclic .
As used herein, the term "optionally substimted heterocyclic(C1-C18)alkyl" refers to a heterocyclic(C1-C18)alkyl group as previously defined substimted in the heterocyclic group with one or more substimtents defined above for heterocyclic and/or substituted in the alkyl group with one or more substitutents defined above for (C1-C18)alkyl. Examples of such groups are (substimted heterocyclic)-lower-alkyl such as (substituted heterocyclic)methyl, (substituted heterocyclic)ethyl, (substimted heterocyclic)propyl, (substimted heterocyclic)iso-propyl, (substimted heterocyclic)butyl, (substimted heterocyclic)pentyl and (substimted heterocyclic)hexyl, heterocyclic(substituted loweralkyl) such as pyrrolyl(substimted loweralkyl), indolyl(substituted loweralkyl), quinolyl(substituted loweralkyl), tetrahydroquinolyl(substituted loweralkyl), pyridyl(substimted loweralkyl), morpholinyl(substituted loweralkyl), piperidinyl(substituted loweralkyl), thiomorpholinyl(substituted loweralkyl), thienyl(substituted loweralkyl), furanyl(substituted loweralkyl), benzfuranyl(substituted loweralkyl), pyrrolidinyl(substituted loweralkyl) and iso-quinolyl(substituted loweralkyl), and (substimted heterocyclic) (substimted loweralkyl), wherein in each case substimted heterocyclic is as exemplified above with respect to "optionally substimted heterocyclic" and (substimted loweralkyl) is as exemplified above with respect to "optionally substimted (C1-C18)alkyl".
As used herein, the term "optionally substimted heterocyclic(C1-C18)alkenyl" refers to a heterocyclic(C1-C18)alkenyl group as previously defmed substimted in the heterocyclic group with one or more substimtents defmed above for heterocyclic and/or substimted in the alkenyl group with one or more substimtents defined above for (C1-C18)alkenyl. As used herein, the term "optionally substimted heterocyclic(C1-C18)alkynyl" refers to a heterocyclic(C1-C18)alkynyl group as previously defined substimted in the heterocyclic group with one or more substimtents defined above for heterocyclic and/or substituted in the alkynyl group with one or more substitutents defmed above for (C1-C18)alkynyl.
As used herein, the term "optionally substituted alkylidene" refers to an alkylidene radical as previously defined, in which one or more hydrogen atoms is replaced by substituent(s) independently selected from the substituents defined above in connection with "optionally substimted (C1-C18)alkyl".
As used herein, the term "namrally occurring or synthetic amino acid" refers to a compound of the formula HN(R401)(CH(R400))pCOOH, wherein R400 and R401 independently have the meaning of R20 as previously defined, and p is 1, 2 or 3, and wherein R400 and R401, together with the carbon and nitrogen to which they are bound may together form a samrated or unsamrated cyclic, bicyclic or fused ring system. Examples of namrally occurring or synthetic amino acids include alanine, cyclohexylalanine, anthranilic acid, arginine, asparagine, aspartic acid, cysteine, β-phenylcysteine, cystine, glutamic acid, glutamine, glycine, cyclohexylglycine, tetrahydrofuranylglycine, histidine, homoserine, hydroxyproline, isoleucine, leucine, lysine, 4-azalysine, δ-hydroxylysine, methionine, norleucine, norvaline, ornithine, phenylalanine, 4-aminophenylalanine, 4-carboxyphenylalanine, 4-chlorophenylalanine, phenylglycine, 8-phenylserine, proline, serine, threonine, trans-3-hydroxyproline, trans-4-hydroxyproline, tryptophan, tyrosine, valine, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, α-aminobutyric acid, α,ɣ-diaminobutyric acid and α,β-diaminopropionic acid. Other amino acids, and peptides derived therefrom, are disclosed in J. S. Davies, ed., Amino Acids and Peptides, Chapman and Hall, London, 1985, the disclosure of which is incorporated herein by reference.
As used herein, the term "residue of a namrally occurring or synthetic amino acid" refers to a group of the formula -N(R401)(CH(R400))pC(O)-, wherein R400, R401 and p are as defined above with regard to "namrally occurring or synthetic amino acid" .
As used herein, the term "azaamino acid" refers to an amino acid in which a -CH(R400)- group has been replaced by a group -N(R401)-, wherein R401 has the meaning of R20 as previously defmed.
Suitable pharmaceutically acceptable salts of the compound of formula (I) are, where the compound of formula (I) contains a basic nitrogen atom, acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, hydrobromic or hydriodic, or with pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, methylmaleic, fumaric, malic, citric, lactic, mucic, gluconic, glucoheptonic, glucaric, glucuronic, lactobionic, benzoic, naphthoic, succinic, oxalic, phenylacetic, methanesulphonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethane-1,2-disulfonic, laurylsulfonic, toluenesulphonic, benzenesulphonic, naphthalene-2-sulfonic, salicylic, 4-aminosalicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric, gly colic, cinnamic, mandelic, 2-phenoxybenzoic, 2-acetoxybenzoic, embonic, nicotinic, isonicotinic, N-cyclohexylsulfamic or other acidic organic compounds, such as 2- or 3-phosphoglycerate and glucose-6-phosphate. Where the compound of formula (I) contains an acid group, suitable pharmaceutically acceptable salts of the compound of formula (I) are addition salts of pharmaceutically acceptable bases such as lithium, sodium, potassium, ammonium, magnesium, calcium and zinc salts, or salts formed with organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, N-methyl-N-ethylamine, mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, tris(hydroxymethyl)methylamine, N,N-dimethyl-N-(2-hydroxyethyl)-amine, tri-(2-hydroxyethyl)-amine, N-methyl-D-glucamine, or tributylamine. Compounds of formula I having acid and basic groups can also form internal salts. Other suitable salts are described, for example, in S. M. Berge, et al , "Pharmaceutical Salts" J. Pharm. Sci., 66 1-19 (1977) which is incorporated herein by reference.
The expression "prodrug" as used herein refers to a pharmaceutically acceptable derivative of a compound of formula (I) which is transformed into a compound of formula (I) after administration of the prodrug to a living animal or human, and which has enhanced stability, delivery characteristics and/or therapeutic value compared to the compound of formula (I) from which it derives.
The expression "protecting group" as used herein refers to a group which may be used temporarily to modify a functional group, for example to prevent that functional group from being affected by, or from undesirably affecting the outcome of, a desired reaction involving another functional group in the molecule and/or to prevent premature metabolism of the compound of formula (I) after administration to a patient before the compound can reach the desired site of action. Suitable protecting groups are described, for example in Greene, T. W., Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 1981) and McOmie, J. F. W., Protective Groups in Organic Chemistry (Plenum Press, London, 1973).
Examples of suitable protecting groups for hydroxyl or mercapto substituents include substimted methyl ethers, for example, methoxymethyl, benzyloxymethyl, t-butyloxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl, benzyl, allyl, triphenylmethyl and the like, other etherifying groups such as 2-tetrahydrofuryl, 2-tetrahydropyranyl and vinyl, or by acyl and carbonate groups such as formyl, 2,2-dichloroacetyl, 2,2,2-trichloroacetyl, t-butyloxy carbonyl, benzyloxycarbonyl, 4-nitrobenzyloxy carbonyl, and 4-methoxybenzyloxycarbonyl, or by silyl groups such as trimethylsilyl, t-butyldimethylsilyl, tribenzylsilyl, triphenylsilyl and the like.
Suitable protecting groups for amino substituents include acyl groups such as formyl, acetyl, 3-phenylpropionyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 4-methoxybenzoyl, t-butyloxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-methoxy benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, (2-pyridyl)methoxycarbonyl, quinoline-2-carbonyl, 2-trimethylsilylethoxycarbonyl, or trimethylsilyl, or an aminoacyl residue.
Suitable protecting groups for carboxyl substituents include esters, for example methyl, ethyl, tert-butyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, methoxymethyl,
2-methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2-trimethylsilylethyl, 2-triphenylsilylethyl, t-butyldimethylsilyl or trimethylsilyl esters.
Suitable protecting groups for carbonyl substituents include acetals such as dimethyl, diethyl, dibutyl and dibenzyl, thioacetals such as S,S-dimethyl and S,S-diethyl, cyclic acetals and thioacetlas such as 1,3-dioxanes, 1,3-dioxolanes, 1,3-oxathiolanes,
1,3-dithianes and 1,3-dithiolanes, and oximes and hydrazones such as O-benzyl oximes,
O-phenylthiomethyl oximes and N,N-dimethyl hydrazones.
The expression "solubilising group Px" as used herein refers to a group which may be used to derivatise a functional group so as to enhance the solubility of the compound of formula (I) in water or aqueous media. Examples of solubilising groups for inclusion in the compound of formula (I) are groups of the formula Px* or salts thereof, where Px* is selected from:
Figure imgf000038_0001
Figure imgf000039_0001
wherein R and R' are independently hydrogen or C1-C4 alkyl. Also included within the meaning of Px are groups of the following formulae, wherein Px* and D are as previously defined, and R is H or C1-C4 alkyl:
Figure imgf000039_0002
Where the compound of formula (I) includes two functional groups capable of being derivatised by a solubilising group, the two funtional groups being in sufficiently close proximity to one another, it will be appreciated that certain of the solubilising groups exemplified above are capable of forming cyclic strucmres, for example including the following structural units:
Figure imgf000039_0003
wherein X1 and X2 are independently selected from O, S and NR6 wherein R6 is as previously defined. Solubilising groups in a cyclic strucmre, such as those exemplifed above, also fall within the meaning of "solubilising group" as used herein.
Where the solubilising group is acidic, a salt thereof is typically a salt of an alkali metal or ammonia, such as Na+, K+ or NH4+. Where the solubilising group is basic, a salt thereof is typically a salt of a strong inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid. Typically, the solubilising group is a sodium or potassium salt of a phosphate or phosphite residue.
Solubilising or protecting groups which are included in the compound of formula (I) must be amenable to hydrolytic or metabolic cleavage in vivo. In one form of the present invention, in the compound of the general formula (I), B is typically selected from the group consisting of
Figure imgf000040_0001
where Z, Z*, M, M1, M2, D*, R14, R14*, R14**, R15, R18, R18*, R19 and R19* are as previously defmed, and V is YR2, Y* or C(R30)=Y**, wherein R2, R30 and Y** are as previously defined, and wherein Y is selected from the group consisting of
Figure imgf000040_0010
s
Figure imgf000040_0005
, , and Y* is selected from the group consisting of
Figure imgf000040_0008
Figure imgf000040_0004
Figure imgf000040_0006
,
Figure imgf000040_0007
and
Figure imgf000040_0009
, wherein R33, R34, R50, R51 and R2* are as previously defined.
More typically, the compound of the general formula (I) in this form of the invention has the strucmre represented by formula (IA):
Figure imgf000040_0003
where R1*, R10, R12, R12*, R13 and R13* are as previously defined, B* is selected from the group consisting of
Figure imgf000040_0002
where Z, Z*, M, M1, M2, D*, R14, R14*, R14**, R18 and R19 are as previously defined, and Yi is selected from the group consisting of
Figure imgf000041_0001
,
Figure imgf000041_0002
and
Figure imgf000041_0003
wherein R50, R51 and R2* are as previously defmed.
Even more typically, the compound of the general formula (I) in this form of the invention has the structure represented by formula (IB):
Figure imgf000041_0004
wherein x and y are independently 0 or 1 ,
B is selected from the group consisting of
Figure imgf000041_0005
wherein R14*, R14**, R15, R18 and R19 are as previously defmed and each R560 is independently hydrogen or (C1-C4)alkyl,
R502 and R506 are independently a group R600, wherein R600 is selected from the group consisting of hydrogen, C(O)OR621, C(O)SR621, C(O)NR621R622, (C1-C6)alkyl, (C2-C6)alkenyl, (C5-C10)cycloalkyl, (C5- C10)cycloalkyl(C1-C6)alkyl, (C5-C10)cycloalkyl(C2-C6)alkenyl, (C6- C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, (C1- C6)acyl, heterocyclic, heterocyclic(C1-C6)alkyl and heterocyclic(C2- C6)alkenyl, each of which may be substimted by up to three substituents selected from the substituents defined above for "optionally substimted (C1-C18)alkyl" and R621 and R622 have the meaning of R21 and R22 respectively, as previously defined, or R621 and R622 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined below,
R501 is selected from the group consisting of R600 as previously defined, S(O)OR632, S(O)2R632, S(O)NR632R633, S(O)2R632R633, NH2, NHR631 and NR631R632, wherein R631 has the meaning of R6 as previously defined and R632 and R633 independently have the meaning of R20 as previously defined, or R501 and R506 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system, or R631 and R632, or R632 and R633 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defmed below,
R512 and R542 independently have the meaning of R600 as previously defined,
R522 and R532 are independently selected from the group consisting of R600 as previously defined, F, Cl, Br and I,
R513 and R543 are independently selected from the group consisting of R600 as previously defmed and R200 as previously defined,
R523 and R533 are independently selected from the group consisting of R600 as previously defined, F, Cl, Br, I, and R200 as previously defined,
R550 has the meamng of R6 as previously defined and R551 is selected from the group consisting of R650, hydrogen, S(O)OR632, S(O)2R632,
S(O)NR632R633 and S(O)2R632R633, wherein R650 has the meaning of R6 as previously defmed and R632 and R633 are as previously defined, or R632 and R633 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defmed below, or R550 and one of R551 and R502 together form a diazaheterocycle wherein R550, R551 or R502 and the two nitrogen atoms to which they are bonded are part of a stable 5 to 10- membered ring which may comprise up to two further heteroatoms selected from O, S and N and to which may be fused one or more cycloalkyl, cycloalkenyl, aryl or heterocyclic residues, which diazaheterocycle may be substimted by one or more of the substituents defmed above for "optionally substimted (C1-C18)alkyl", and wherein two substituents may together form part of a ring,
or one pair selected from R512 and R513, R522 and R523 (when present), R532 and R533 (when present), and R542 and R543, together are =O; wherein, when B is other than or then at least one of
Figure imgf000042_0001
Figure imgf000042_0002
conditions (i) to (xi) below applies:
(i) at least one of R512 and R542 is a group R655, wherein R655 is selected from the group consisting of (C1-C6)alkyl(C6-C10)aryl, (C2-C6)alkenyl(C6-C10)aryl, (C5-C10)cycloalkyl(C2-C6)alkenyl, (C5-C10)cycloalkyl(C6-C10)aryl, acyl(C6-C10)aryl, heterocyclic(C1-C6)alkyl, heterocyclic(C2-C6)alkenyl, heterocyclic(C6-C10)aryl, C(D*)OR21*, C(D*)SR21* and C(D*)NR21*R22*, wherein D*, R21* and R22* are as previously defined, (ii) at least one of R522 and R532, when present, is selected from the group consisting of R655 as previously defmed, F, Cl, Br and I,
(iii) at least one of R513 and R543, when present, is selected from the group consisting of R655 as previously defined, and R200 as previously defined, (iv) at least one of R523 and R533, when present, is selected from the group consisting of R655 as previously defmed, F,Cl Br, I and R200 as previously defined,
(v) R550 is a group R656, wherein R656 is selected from the group consisting of (C1-C6)alkyl(C6-C10)aryl, (C2-C6)alkenyl(C6-C10)aryl, (C5- C10)cycloalkyl(C2-C6)alkenyl, (C5-C10)cycloalkyl(C6-C10)aryl, acyl(C6- C10)aryl, heterocyclic(C1-C6)alkyl, heterocyclic(C2-C6)alkenyl, heterocyclic(C6-C10)aryl,
(vi) R551 is selected from the group consisting of R656 as previously defined,
S(O)OR632, S(O)2R632, S(O)NR632R633 and S(O)2R632R633, wherein R632 and R633 are as previously defined,
(vii) R502 is selected from the group consisting of R65g as previously defined,
C(D*)SR21* and C(D*)NR21*R22*, wherein D*, R21* and R22* are as previously defined,
(viii) R502 and R551 are both hydrogen or are both (C1-C6)acyl,
(ix) R14* is selected from the group consisting of C(D*)OR40, C(D*)SR40 and C(D*)NR40R41, wherein R40 and R41 are as previously defmed,
(x) R501 is selected from the group consisting of R656 as previously defmed,
S(O)OR632, S(O)2R632, S(O)NR632R633, S(O)2R632R633, NH2, NHR631 and NR631R632, wherein R632 and R633 are as previously defmed, (xi) R501 and R506 are both (C1-C6)acyl, and wherein when B is or then at least one of the
Figure imgf000043_0001
Figure imgf000043_0002
following conditions also applies:
(xii) x + y > 0,
(xiii) x + y = 0 and at least one of R532 and R533 is other than hydrogen,
(xiv) R50 and R51 together form a diazaheterocycle as previously defmed,
(xv) at least one of R501, R502, R506 and R551 is optionally substituted heterocyclic(C1-C18)alkyl, and
(xvi) at least one of R512, R542, R522, R532, R513, R543, R523 and R533 is selected from the group consisting of C(O)OR621, C(O)SR621 and C(O)NR621R622, wherein R621 and R622 are as previously defined.
Examples of typical unsubstituted diazaheterocycles are:
Figure imgf000044_0001
Other forms of the first embodiment of the invention have the strucmres represented by formulae (IC) to (IAW) below, in which each AA is independently a residue of a namrally occurring or synthetic amino acid as herein defined; R1*, R1, X and X* are as previously defmed; Ra to Rj independently are -(CH2)a-6OPy, wherein a can be 0, 1, 2, 3, 4 or 5, halogen or R6, more typically -(CH2)0.3OPy, fluoro, chloro or R6* wherein Py is a solubilising group Px as defined herein, R6 is as previously defined and R6* is is selected from the group consisting of
hydrogen,
R20*, wherein R20* is selected from the group consisting of
optionally substimted (C1-C6)alkyl,
optionally substituted (C2-C6)alkenyl,
optionally substimted (C2-C6)alkynyl,
optionally substimted (C3-C8)cycloalkyl,
optionally substimted (C3-C8)cycloalkyl(C1-C6)alkyl,
optionally substimted (C3-C8)cycloalkyl(C2-C6)alkenyl, optionally substimted (C3-C8)cycloalkyl(C2-C6)alkynyl, optionally substimted (C6-C10)aryl,
optionally substimted (C6-C10)aryl(C1-C6)alkyl, optionally substimted (Cg-C10)aryl(C2-C6)alkenyl,
optionally substituted (C1-Cg)acyl,
optionally substimted heterocyclic, and
optionally substituted heterocyclic(C1-Cg)alkyl,
C(O)OR21,
C(O)SR21, and
C(O)NR21R22, wherein R21 and R22 independently are selected from hydrogen and R20* as previously defined, or R21 and R22 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as previously defined:
Figure imgf000045_0001
wherein D' is O or S, and each G is independently hydrogen or R200 as previously defmed and wherein R'd and R'f are Rd and Rf or, taken together, may be trimethylene or tetramethylene optimally substituted with -C(O)OR; or -C(O)NRiRj;
Figure imgf000045_0002
wherein G is selected from R1* and X*R1*;
Figure imgf000045_0003
wherein Ra' is OPy or R6 as previously defined, M1 is R6 as previously defined, (CH2)1- 2OPy or (CH2)1-2NHPy, and G* is OR2 or NRiR2;
Figure imgf000046_0001
;
Figure imgf000046_0002
wherein G is hydrogen, Ra, R1*X* or R1*X*C(Ra)(Rb)C(O), and wherein Ra, R1*, and the atoms to which they are bound may optionally form a samrated or unsamrated cyclic, bicyclic or fused ring system;
Figure imgf000046_0003
wherein Ra, R1*, and the atoms to which they are bound may optionally form a saturated or unsamrated cyclic, bicyclic or fused ring system;
Figure imgf000046_0004
wherein W2 is R1X or R6 as previously defined, and R' is Py or R6 as previously defmed, or R1 and Py, taken together with the oxygen atoms to which they are attached form a group selected from , and
Figure imgf000046_0005
Figure imgf000046_0006
Figure imgf000046_0007
Figure imgf000047_0001
wherein each L is independently as previously defined and each Pz is independently hydrogen or Py, provided that at least one Pz is Py or, when each Pz is Py, the groups Py, together with the oxygen atoms to which the are bound define a cyclic group selected from
Figure imgf000047_0002
- , and ;
Figure imgf000047_0003
Figure imgf000047_0004
Figure imgf000047_0005
wherein Q is O or NRf and G is R1* or X*R1*;
Figure imgf000047_0006
wherein each is independently a 5- or 6- membered samrated or unsamrated
Figure imgf000047_0007
heterocycle containing a nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, oxygen and sulfur, and wherein Ra' and Rb' independently have the meaning of -(CH2)0-6OPy or R6, or taken together are = O;
Figure imgf000047_0008
wherein W1 is selected from R1X and R1*X*, and Q is selected from O and NRh;
Figure imgf000048_0001
wherein W1 is selected from R1X and R1*X*, each Pz is independently hydrogen or Py, provided that at least one Pz is Py, and Q is selected from O and NRh;
Figure imgf000048_0002
wherein each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
Figure imgf000048_0003
wherein is a 5- or 6- membered samrated or unsamrated heterocycle containing a
Figure imgf000048_0004
nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, o oxygen and sulfur;
Figure imgf000048_0005
wherein Ra' and Rj' are independently selected from R 1 and R1*, as previously defined;
Figure imgf000049_0001
wherein G is selected from , and a saturated or unsaturated
Figure imgf000049_0002
Figure imgf000049_0003
cyclic, bicyclic or fused ring system, Q is O or NH, and G* is X or X* as previously defined;
Figure imgf000049_0004
wherein is a 5-12 membered samrated or unsamrated cyclic, bicyclic or fused
Figure imgf000049_0005
ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur;
Figure imgf000049_0006
wherein G is selected from hydrogen and R1*X*, Q is O, S or NH, Q* is O or NH, and G1 is selected from R1 and R1*X*;
Figure imgf000049_0007
wherein R200 is as previously defmed;
Figure imgf000050_0001
wherein is an optionally substituted 5-12 membered samrated or unsamrated
Figure imgf000050_0002
cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur;
Figure imgf000050_0003
wherein b is 0, 1 or 2, provided that at least one b is greater than 0, and each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
Figure imgf000050_0004
wherein each G* is independently selected from O, S and NR6 and G is selected from OR6, NHR6 and R20;
Figure imgf000050_0005
wherein G is -C(O)- or -CH2-, G* is R2 or R1*, G** is -O- or -NRh-, Q is -O- or -NRi and Pz is selected from the group consisting of
Figure imgf000050_0006
Figure imgf000050_0007
Figure imgf000051_0001
wherein R and R' are independently hydrogen or C1-C4 alkyl, D is O or S and Px* is as previously defined;
Figure imgf000051_0002
wherein G is R1 or R1*, G* is -O- or -NRf- and Pz is selected from the group consisting
Of
Figure imgf000051_0003
Figure imgf000051_0004
wherein R and R' are independently hydrogen or C1-C4 alkyl, D is O or S and
Px* is as previously defined;
Figure imgf000051_0005
wherein G is R1 or R1*, and each Q is independently H, -OPz or -NP dPz, wherein each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
Figure imgf000052_0001
wherein is a saturated or unsamrated cyclic, bicyclic or fused nitrogen
Figure imgf000052_0002
containing ring system and G is a bond or is -O- or -NRf ;
Figure imgf000052_0003
wherein G is absent or X*R1* and is a 3 to 10-membered samrated or unsamrated
Figure imgf000052_0004
heterocycle containing a nitrogen atom and optionally additionally one to three heteroatoms selected from nitrogen, oxygen and sulfur;
Figure imgf000052_0005
wherein Q is selected from -O-, -S- and -NRf-;
Figure imgf000052_0006
wherein G is O, S, S(O) or S(O)2, and Ra' and Rb' have the meamng of Ra and Rb or Ra ' and Rb' together are trimethylene or tetramethylene;
Figure imgf000052_0007
wherein each Ar is independently (C6-C14)aryl, R'c and R'd are Rc and Rd or, taken together, are -C(O)- or -CH(OH)-, and wherein Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from
Figure imgf000053_0001
,
Figure imgf000053_0002
and
Figure imgf000053_0003
;
Figure imgf000053_0004
wherein G is a bond or X as previously defined, Rg' and Rh' are Rg and Rh or together form a samrated or unsamrated cylic, bicylic or fused ring system, and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from
Figure imgf000053_0005
,
Figure imgf000053_0006
and
Figure imgf000053_0007
;
Figure imgf000053_0008
wherein G is a bond, O, S or NRj, Rg' and Rh' are Rg and Rh, or taken together may be - C(O)-, and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from
Figure imgf000053_0009
,
Figure imgf000053_0010
and
Figure imgf000053_0011
;
Figure imgf000053_0012
wherein G is OPy, NHRe, NPyRe or Re;
Figure imgf000054_0001
wherein G and G* are independently a bond, O, S or NH, and R'd and Rh' are Rd and Rh or taken together are -CR'2- or -CR2'-CR2'- wherein each R' independently has the meaning of R6 as previously defined, Q and Q* are independently N or CR6, or when Q* is CR6 then Rg and R6 together may be a double bond;
Figure imgf000054_0002
wherein G is -C(O)- or -C(R6)(CH2)0-4OG* wherein G* is R6 or Py;
Figure imgf000054_0003
;
Figure imgf000054_0004
wherein G is selected from hydrogen and X*R1* and wherein represents a 4-10
Figure imgf000054_0005
membered samrated or unsamrated cyclic, bicylic or fused ring system as defined herein;
Figure imgf000054_0006
wherein Q is selected from O, S and NRg, G and G* are independently selected from R1, R1*, -C(R5)=NR3 and -C(R5)=NOR3, wherein R3 and R5 are as previously defined, R'e and R'f are Rg and Rf, and G** is R20 as previously defined;
Figure imgf000055_0002
wherein each Rz is independently selected from Ri and PyOG* wherein G* is optionally substimted alkylelne, provided that at least one Rz is PyOG*, and G is -NRd- or CRdRe-;
Figure imgf000055_0001
wherein
Figure imgf000055_0005
represents an optionally substituted saturated or unsaturated ring system optionally containing up to three heteroatoms selected from N, O and S, G is selected from R1, XR1 or X*R1* and Ra and Rb taken together may optionally be -C(O)-;
Figure imgf000055_0004
wherein B* is a group B, as previously defeined, derivatised with a solubilising group Py;
Figure imgf000055_0003
wherein
Figure imgf000055_0006
represents an optionally substimted cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 3 heteroatoms selected from N, O and S;
Figure imgf000056_0001
wherein Q1 and Q2 are independently selected from O and S, and R'f and R'g are respectively Rf and Rg or are selected from OR' , SR' and NRhR' wherein R' is H, Ri or
Py;
Figure imgf000056_0002
wherein each G is independently selected from O and NRj, and R' is (CH2)1_2OPy or R6;
Figure imgf000056_0003
wherein G and G* are independently selected from
Figure imgf000056_0004
,
Figure imgf000056_0005
and L, wherein L is as previously defined and Q is H or Py, provided that at least one of G and G* is other than L and provided that at least one Q is Py, or wherein two groups OQ taken together are a cyclic group sleeted from
Figure imgf000056_0006
,
Figure imgf000056_0007
and
Figure imgf000056_0008
Figure imgf000056_0009
wherein Rx and Ry are independently R6 or (CH2)1-2OPy;
Figure imgf000057_0001
wherein G and G* are independently selected from R1, R1*, -C(R5)=NR3 and -C(R5)N=OR3, wherein R3 and R5 are as previously defined.
Still other compounds of the first embodiment are those compounds exemplified in International Patent Application no. WO 93/18006, namely:
(i) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate ,
(ii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-valyl)amino-4-phenylbutyl] carbazate,
(iii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbuty 1] carbazate ,
(iv) t-butyl 3-(1-methyl-3-phenylpropen-3-yl)-3-[(2R or S, 3S)-2-hydroxy-3- (phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate,
(v) t-butyl 3-(1-methyl-3-phenylpropyl)-3-[(2R or S, 3S)-2-hydroxy-3-(N- quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate,
(vi) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane,
(vii) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbuty1]-diazabicyclo[4.4.0]decane,
(viii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- valyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane,
(ix) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-[N-(2-pyridyl)- methoxycarbonyl)-L-valyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane,
(x) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane, (xi) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- glutaminyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane, (xii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- threonyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane,
(xiii) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]nept-5-ene,
(xiv) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1]heptane, (xv) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2-pyridyl)methoxy-L- valyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1]heptane,
(xvi) 2-[N-(lS)(2-methyl-l-methoxycarbonylpropyl)carbamoyl]-3-[(2R or S, 3S)-2- hydroxy-3-[N-(2-pyridyl)methoxy-L-valyl]amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]heptane,
(xvii) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]heptane,
(xviii) 1-[2-(2-pyridyl)methoxycarbonylamino-]benzoyl-2-[(2R or S, 3S)-2-hydroxy- 3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-2-isopropyl-hydrazine, (xix) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-l ,2,3 ,4-tetrahydrophthalazine,
(xx) 1-trimethylacetyl-2-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phyeny lbutyl] -2-isopropy lhy drazine ,
(xxi) 1-trimethylacetyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl) amino-4-pheny lbutyl] -2-isopropy lhy drazine ,
(xxii) 1-(t-butylamino)carbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-pheny lbutyl] -2-isopropy lhy drazine ,
(xxiii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-picolinoyl-L- asparaginyl)amino-4-pheny lbutyl] carbazate,
(xxiv) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2-pyridyl)-methoxycarbonylanthraniloyl)amino-4-phenylbutyl]carbazate.
(xxv) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-pheny lbutyl] carbazate ,
(xxvi) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-pheny lbutyl] carbazate,
(xxvii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenyl-methoxycarbony l)amino-4-pheny lbutyl] carbazate ,
(xxviii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]carbazate,
(xxix) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(l-carbamoyl-methyl)acryloyl)amino-4-phenylbutyl]carbazate,
(xxx) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio¬
2-carbamoyl-methy lpropiony l)amino-4-pheny lbutyl] carbazate,
(xxxi) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(1-benzoyl-L- asparaginyl)amino-4-pheny lbutyl] carbazate ,
(xxxii) 1-t-butyloxycarbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]hexahydropyridazine,
(xxxiii) 1-t-butyloxycarbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]hexahydropyridazine, and (xxxiv) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl¬
3-cyano-L-alanyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4,4,0]decane, wherein the 2-hydroxy group has been derivatised with a solubilising group Px as herein defined. Typically, in this form of the first embodiment, compounds (i) to (xxxiv) referred to above are derivatised with a solubilising group selected from and
Figure imgf000059_0001
.
Figure imgf000059_0002
The compounds of formulae (I) to (LAW) can exist in optically isomeric forms and the present invention includes within its scope all these forms in all proportions including all diastereoisomers and mixtures thereof and all enantiomers, mixtures of enantiomers and racemic mixtures. Where a double bond occurs in the compound of the invention, the double bond may be present in the cis- (Z) or trans- (E) configuration. It will be understood that only compounds of formula (I) with combinations of substituents or functional groups which give rise to stable compounds, are within the scope of the present invention.
The compounds of general formula (I) may be prepared by methods known generally in the art. Suitable methods for the synthesis of compounds of formula (I) and intermediates thereof are described, for example, in Houben-Weyl, Methoden der Organischen Chemie; J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley & Sons, New York, 1985); D. C. Liotta and M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley & Sons, Inc., New York, 1991); R. C. Larock, Comprehensive Organic Transformations (VCH, New York, 1989), H. O. House, Modern Synthetic Reactions 2nd Edition (W. A. Benjamin, Inc., Menlo Park, 1972); N. S. Simpkins, ed. 100 Modern Reagents (The Royal Society of Chemistry, London, 1989); A. H. Haines Methods for the Oxidation of Organic Compounds (Academic Press, London, 1988) and B. J. Wakefield Organolithium Methods (Academic Press, London, 1988).
For example, a compound of formula (I) may be prepared from synthons W*, {(A)n-B-(A*)m}* and V*, wherein each synthon identified thus * is a synthetic precursor of the corresponding portion of the molecule W-(A)n-B-(A*)m-V. Thus, a compound of formula (I) may be prepared, for example, in any of the following ways:
(a) by reaction of W-(A)n-B-(A)m-G with H-V;
(b) by reaction of W-(A)n-B-(A)m-H with G-V;
(c) by reaction of W-H with G-(A)n-B-(A)m-V; and
(d) by reaction of W-G with H-(A)n-B-(A)m-V;
wherein G is a leaving group such as halogen, typically chlorine, bromine or iodine; a sulfonate such as methanesulfonate, trifluoromethanesulfonate, benzenesulfonate or toluenesulfonate; an alkoxy, thioalkoxy, aryloxy or thioaryloxy group such as ethoxy, methoxy, thiomethoxy or phenoxy; acyloxy such as acetyl, trifluoroacetyl or benzoyl; hydroxy; amino or protonated amino; nitrate; phosphate; borate and the like. If appropriate these reactions may be carried out in the presence of a base such as triethylamine, pyridine or other tertiary amine, butyllithium, sodium tert-butoxide or similar, and/or a coupling reagent such as a carbodiimide.
When V is YR2 where Y is — N=N— , or when V is Y* where Y* is a member of the group
Figure imgf000060_0001
,
Figure imgf000060_0002
and
Figure imgf000060_0003
, the compound of formula (I) may be prepared as shown in Scheme 1 or Scheme la. In the Schemes and in the Examples herein, the terms Me, Et. Pr, Ph and Bz signify methyl, ethyl, propyl, phenyl and benzyl respectively and the following additional abbreviations are used:
THP tetrahydropyranyl,
t-Bu or But tertiary butyl
n-Bu n-butyl
iPr or Pri isopropyl
Hal halogen; i.e. , fluorine, chlorine, bromine or iodine
Ts para-toluenesulfonyl
DMF dimethyl formamide
CDI N,N'-carbonyldiimidazole
BOP benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate
HBT 1-hydroxybenzotriazole
AcCN acetonitrile
DMSO dimethyl sulfoxide
Py.xSO3 pyridine/sulfur trioxide complex
QC quinoline-2-carbonyl
PC 2-pyridinemethoxycarbonyl
MC N-morpholinocarbonyl
TMC N-thiomorpholinocarbonyl
Val valinyl
Asn asparaginyl
Ile isoleucyl
Gly glycinyl
Glu glutaminyl
Thr threonyl
Ala alanyl (CN)Ala cyanoalanyl
(p-F)Bz 4-fluorobenzyl
(p-CN)Bz 4-cyanobenzyl
Z benzyloxycarbonyl
Boc t-butyloxycarbonyl
Ac acetyl
TFA trifluoroacetyl
C6H11 cyclohexyl.
Figure imgf000061_0001
Other compounds of formula (I) may be prepared analogously, by reacting a synthon W-(A)n-B-(A*)m-Hal with HV, if appropriate in the presence of a strong base.
Figure imgf000062_0002
In Scheme 1a, R represents an alkyl, aryl or aralkyl group, such as t-butyl, phenyl or benzyl. Suitable bases include pyridine, triethylamine and other tertiary amines, alkali metal carbonates and alkali metal hydroxides. The moiety W-(A)n-B-(A*)m- may be represented by Ra, in which case Rb represents R50 as previously defined, and Rc represents R2 as previously defmed, or W-(A)n-B-(A*)m- may be represented by Rc, in which case R5 represents R51 and Ra represents R2.
When V is Y* where Y* is , the compound of formula (I) may be
Figure imgf000062_0003
prepared from by reacting a hydrazine wherein R51 and R2* are both hydrogen, which may be prepared as shown in Scheme 1 or Scheme la, with an aldehyde or ketone.
When V is YR2 where Y is or , the compound of formula
Figure imgf000062_0004
Figure imgf000062_0005
(I) may be prepared as shown in Scheme lb
Figure imgf000062_0001
When V is YR2 where Y is a member of the group
Figure imgf000063_0001
the compound of formula (I) may be synthesised by coupling a synthon W-(A)n-B-(A*)m- Za with a synthon Zb, where Za includes one of the heteroatoms of Y, and Zb includes the other heteroatom or atoms, as shown in schemes 2a and 2b:
Figure imgf000064_0001
Figure imgf000065_0001
Analogous methods may be used to obtain the corresponding thionophosphates and thionophosphonates.
When V is C(R30)=Y** the compound of formula (I) may be prepared from a synthon having a ketone or aldehyde function, by condensation with a substimted hy drazine or substimted hydroxylamine corresponding to Y**.
When V is Y*, where Y* is -N=O, the compound of formula (I) may be prepared by oxidising the corresponding primary amine, for example with Caro's acid, or H2O2 in acetic acid, or H2O2 with sodium tungstate. It will be appreciated that a compound of formula (I) wherein Y* is -N=O will only be isolable as a nitroso compound when the carbon atom bearing Y* has no α-hydrogens.
When V is Y* where Y* is or , the compound of formula
Figure imgf000066_0001
Figure imgf000066_0002
(I) may be prepared by oxidation of the corresponding thioether
W-(A)n-B-(A*)m-S-R114* (IV)
with hydrogen peroxide and acetic acid. The thioether (IV) may be synthesised by coupling a halide W-(A)n-B-(A*)m-Hal with a thiol R114* under basic conditions, or by reacting a disulfide R114*SSR114* with an organolithium reagent W-(A)n-B-(A*)m-Li derived from the corresponding halide.
When V is Y*, where Y* is or , the compound of formula
Figure imgf000066_0003
Figure imgf000066_0004
(I) may be prepared by the Arbuzov reaction as shown in scheme 3:
Figure imgf000066_0005
The synthon W-(A)n-B-(A*)m-Z, where Z is any of the functional groups bound to (A*)m which are represented in schemes 1 to 3, may be prepared by coupling a suitably fiinctionalised fragment W* with a correspondingly fiinctionalised fragment Z*-(A)n-B- (A*)m-Z. Alternatively, the compound of formula (I) may be synthesised by first coupling V to (A)n-B-(A*)m- as described above with reference to schemes 1 to 3, and then coupling the resulting molecule to a fiinctionalised fragment W*. Methods for coupling a precursor of group W with a fiinctionalised fragment Z*-(A)n-B-(A*)m-Z are well known in the art, and include methods analogous to those represented in schemes 1 to 3. For example, when W is R1X and X is Y, the coupling may be achieved as described in schemes 1 to 3 above. When W is R1X and X is NR10, O or S, the coupling may be achieved by any of the known methods for the alkylation of amines, and the synthesis of ethers and thioethers, respectively. That is, the coupling may be achieved by reacting a fragment Z*-(A)n-B-(A*)m-Z wherein Z* is a leaving group such as halogen, sulfonate ester, acetate or frialkylammonium salt, with R1R10NH, R1OH or R1SH, if necessary in the presence of strong non-nucleophilic base such as butyllithium, sodamide or potassium tert-butoxide. Compounds in which X is S(O) or S(O)2 may be prepared by the oxidation of the corresponding compound in which X is S. Compounds in which W is -CN, -C(R5)=NR3, -C(R5)=NOR3, -C(D)OR3, -C(D)SR3 or -C(D)NR3R4 may be prepared from the fragment Z*-(A)n-B-(A*)m-Z wherein Z* is an aldehyde, ketone or carboxyl group as shown in Scheme 3a.
Figure imgf000067_0001
Compounds in which W is -N=CR5R5* may be prepared by reacting the fragment Z*-(A)n-B-(A*)m-Z, where Z* is NH2, with an aldehyde or ketone having group(s) R5 and R5* bound to the carbonyl.
The fragment Z*-(A)n-B-(A*)m-Z may be prepared by methods which depend on the nature of B. Where B is a substimted carbon atom, the fragment may be conveniently prepared from a fragment E-C(O)-E*, in which E is a fragment Z*-(A)n and E* is a fragment (A*)m-Z, as shown in scheme 4:
Figure imgf000068_0001
Fragments which are starting materials for compounds of formula
Figure imgf000068_0002
(I) are known compounds or analogs of known compounds which can be prepared by methods analogous to methods used for preparation of the known compounds. The synthesis of known fragments may be found with reference, for example, to
Figure imgf000068_0003
Beilsteins Handbuch der Organischen Chemie or to J. Buckingham, ed., Dictionary of Organic Compounds 5th Edition (Chapman & Hall, New York, 1982). Alternatively, a functionalised group E may be coupled to a group E*C(O)H, or a fiinctionalised group E* may be coupled to a group EC(O)H, followed by oxidation. For example, a halide EBr may be coupled to E*C(O)H with an organolithium or organomagnesium reagent derived from EBr, followed by oxidation of the resulting secondary alcohol to the corresponding ketone, if desired. Alternatively a carboxylic acid EC(O)OH may be converted to an activated derivative, such as an ester or amide: for example an amide obtained by reaction of the carboxylic acid with N,O-dimethyl hydroxy lamine hydrochloride in the presence of a carbodiimide and tertiary base, followed by addition of an organolithium or organomagnesium reagent derived from E*Br, E*C1 or E*I.
When B is an epoxide of the type the fragment E-B-E* may be
Figure imgf000069_0001
prepared from the corresponding olefin by reaction with a per-acid such as trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid. Suitable olefins for conversion to the fragment E-B-E* are commercially available or may be synthesised by known methods, for example by means of the Wittig reaction or by an elimination reaction of an alcohol, alcohol sulfonate, ester, halide or the like. When B is a diol of the type , the compound of formula (I) may
Figure imgf000069_0002
conveniently be prepared by reductive coupling of aldehydes EC(O)H and E*C(O)H as described in J. Org. Chem 55, 4506 (1990) and U.S. Patent No. 5,294,720.
When B is a heteroatom or substimted heteroatom, the fragment Z*-(A)n-B-(A*)m-Z is a substimted amine, phosphine or phosphine oxide, or is an ether, thioether, sulfoxide or sulfone. Substimted amines, ethers, thioethers, sulf oxides and sulfones may be prepared as described above. Secondary or tertiary phosphines may be prepared by alkylation of the corresponding primary or secondary phosphine as described, for example, in J. D. Roberts and M. C. Caserio, Basic Principles of Organic Chemistry (W.A.Benjamin, Inc., New York, 1965).
In any of the reactions described above, it may be necessary to protect reactive group(s) in the compound of formula (I) other than those participating in a desired coupling or oxidation reaction using suitable protecting group(s) in order to carry out the desired coupling or oxidation reaction without chemically affecting those reactive groups. Suitable protecting groups for this purpose are described in the works of Greene and McOmie referenced above.
The compounds of formula (IB) wherein x and y are both 1 may be prepared as generally described above. A compound of formula (IB) which is
Figure imgf000069_0003
where Ra and Rb, have the meaning of R501 and R506 as previously defined and Rc and Rd have the meaning of R551 and R502 as previously defined, may be prepared from ethylene cyanohydrin by the method shown in Scheme 5.
Figure imgf000070_0001
A substituted compound of formula (IB) may be prepared by the general method of Scheme 5, with the substiments R512, R513, R522, R523, R532, R533, R542, R543 and R550 being introduced, as desired, into the compounds of formula (Va), (Vb), (Vc) and (Vd) shown in Scheme 5 by the methods illustrated in Scheme 5a.
Figure imgf000071_0001
In reaction 5a-1 shown above, it will be appreciated that the step of introducing the second substituent R' will only be carried out if it is desired that both R522 and R523 be other than hydrogen. The reactions shown in 5a-2 and 5a-3 may be repeated, if desired, so as to introduce a second substituent on the carbon atom bearing R" or R"C(O). The second substituent can be the same as or different from the first. Where one or both of R522 and R523 is acyl, this group may be introduced as shown in reaction 5a-3 with respect to compound (Vb). Where R522 and R523 are both hydrogen, the reactions shown in 5a-2 and 5a-3 may give mixmres of products and in that case it may be preferable to introduce the desired groups R532, R543, R542 and R543 by replacing the ethylene bromohydrin shown in Scheme 5 with a suitably substimted bromohydrin obtained from the corresponding olefin as shown in Scheme 5b. It will be appreciated that the nature of the groups Rs32, Rs43, Rs42 and R543 will determine the stereochemistry of the addition of HOBr to the olefin and of the opening of the epoxide.
Figure imgf000072_0001
Compounds of formula (IB) wherein B is other than -CH(OH)- may be prepared by the methods shown in Scheme 4 after oxidation of the secondary alcohol to the corresponding ketone.
The compounds of formula (IB) wherein B is a substimted carbon atom and y is 0 can be prepared by reacting a compound of formula (II), (II A) or (IIB)
Figure imgf000072_0002
wherein R14*, R501, R502, R506, R512, R513, R522, R523, R542 and R543 have the significance given earlier and Hal is a group selected from -Cl, -Br or -I, with a compound of formula (III)
Figure imgf000072_0003
wherein R502, R550 and R551 have the significance given earlier. Where a compound of formula (II) is used, the reaction may be followed by oxidation of the resultant secondary alcohol to the corresponding ketone. This ketone may be used for elaboration of the substituents on B as shown in Scheme 4.
A compound of formula (II), (II A) or (IIB) may be prepared from a β-amino acid or a β-amido acid as shown in Scheme 6. A compound of formula IIl may be prepared as shown in Scheme 1a.
Figure imgf000073_0001
An alternative route to the β-aminoaldehyde shown in Scheme 6 is by reduction of the methyl ester of the corresponding β-amino acids using diisobutylaluminium hydride.
β-amino acids, or β-amido acids, may conveniently be prepared by the Mannich reaction of an amine or amide with an enolisable ketone in the presence of formaldehyde or another aldehyde.
A compound of formula (IB) wherein x and y are both 0 may be prepared by reacting a compound of formula (EC) or (IID)
Figure imgf000074_0002
with a compound of formula (III) as shown above. An analogous procedure, utilising a primary or secondary amine rather than a hydrazine as shown in formula (III) yields a hydroxy diamine. A compound of formula (IIC) may be prepared from an α-amino acid by a method analogous to that shown in Scheme 6, such as described in the following:
Evans, B.E., et al., J. Org. Chem. , 50, 4615-4625 (1985);
Luly, J.R., et al., J. Org. Chem. , 52, 1487-1492 (1987);
Handa, B.K., et al., European Patent Application No. 346,847-A2 (1989) and
Marshall, G.R., et al., International Patent Application No WO91/08221.
Suitable α-amino acids may be prepared, for example, by the Strecker synthesis, starting from an appropriate ketone. The overall route to the compound of formula (IIC) is shown in Scheme 7. Other suitable methods are described in Coppola, et al. Asymmetric Synthesis. Construction of Chiral Molecules using Amino Acids (Wiley Interscience, New York, 1987).
Figure imgf000074_0001
Where W is a nitrogen-containing group, and one of R1 and R10 is a protected amino acid residue, the coupling of the protected amino acid residue may be accomplished as shown in Scheme 8, in which the amino acid (designated AA) protecting group is benzyloxycarbonyl, designated Z. Methods for the formation of peptide bonds and for the protection of peptide residues are described, for example, in Gross and Meienhofer, eds. , The Peptides, (Academic Press, New York, 1983). Suitable other coupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and diphenylphosphoryl azide (DPPA).
Figure imgf000075_0001
Numerous synthetic routes exist to substimted hydrazines, including the hydrazines of formula (III), useful in the synthesis of compounds of formula (I). The hydrazine intermediates (III) can be obtained using known methods such as those described in the following:
Dutta, A.S., et al., J. Chem. Soc. Perkin Trans. I, (1975) 1712-1720,
Ghali, N.I., et al., J. Org. Chem. , 46, 5413-5414 (1981),
Gante, J., Synthesis (1989) 405-413 and
Houben-Weyl's Methoden der Organische Chemie, vol. 16a, Part 1, pp 421-855;
Georg Thieme Verlag, Stuttgart (1990)
Other methods for preparing substimted hydrazines are illustrated in Scheme 9.
Figure imgf000075_0002
Compounds of formula (I) wherein a group selected from R1, R1*, R2, R2*, R9, R11, R12, R50 and R51, together with another group selected from R1, R1*, R2, R2*, R9*, Rio, R11, R12, R50 and R51 forms a cyclic, bicyclic or fused ring system may be prepared by variants on the above methods which will be readily apparent to persons skilled in the art in the light of the foregoing. An example of a method of preparing one class of cyclic compounds of formula (I) is presented in Scheme 10:
Figure imgf000076_0001
Compounds in accordance with the present invention which do not include a solubilising group Px typically exhibit low to very low water solubility. Inhibitors of
HIV proteases which have hitherto been described, and many other pharmaceutically or veterinarily active substances also typically exhibit low to very low water solubility. This property tends to cause the bioavailability of such substances to be relatively low. There is thus a need for a HIV protease inhibitor having enhanced water solubility.
Surprisingly, it has been found that the inclusion of a solubilising group Px as defined herein in a substance having low to very low water solubility results in enhancement of the water solubility of the substance. Thus, substances in accordance with the invention which include a solubilising group Px exhibit superior bioavailability, including superior oral bioavailability, compared to compounds in accordance with the invention which do not include a solubilising group Px.
Thus, according to a second embodiment of the present invention, there is provided process for enhancing the water-solubility of a pharmaceutical or veterinary substance, comprising derivatising a functional group of said substance with a solubilising group Px,
wherein Px is selected from the group consisting of Px*,
Figure imgf000077_0003
Figure imgf000077_0002
, and wherein D is O or S, R is H or C1-C4 alkyl, and wherein Px* is selected from:
O
Figure imgf000077_0001
said functional group being capable of being derivatised with said solubilising group Px.
Generally, a compound according to the first embodiment includes at least one solubilising group Px as defined above. More generally, a solubilising group in a compound of the first embodiment or in the method of the second embodiment is selected from and .
Figure imgf000077_0004
Figure imgf000077_0005
Typically, a solubilising group is introduced into the molecule as the last stage of its synthesis. For example, a solubilising group P(O)(OH)2 may be introduced to a free amino, hydroxy or mercapto group by reaction of the amino, hydroxy or mercapto group with dimethyl chlorophosphate, followed by mild hydrolysis to remove the methyl ester groups. Other solubilising groups referred to above may be introduced by analogous methods: that is, by reaction of an amino, hydroxy, mercapto or other group capable of being derivatised with a solubilising group, with a reagent PxX' , suitably protected if necessary (for example as methyl or benzyl esters), wherein Px is as defined above and X' is a leaving group such as Cl, Br, OH, OS(O)2R and the like, where R is C1-C6 alkyl, for example methyl, C6-C10 aryl, for example phenyl or 4-methylphenyl, or C7-C11 arylalkyl, for example benzyl. Alternatively, a solubilising group P(O)(OH)2 may be introduced to a free hydroxy group by reaction with phosphorous acid and mercuric salts in the presence of a tertiary amine, as described by Obata and Mukaiyama in J. Org. Chem. , 32, 1063 (1967). As a further alternative, an amino, hydroxyl or mercapto group may be reacted with phosphorous acid preferably in the presence of a coupling agent such as dicyclohexylcarbodiimide and pyridine to yield a molecule possessing the solubilising group -OP(O)(OH)H. Optionally, this group may be oxidised to the corresponding phosphate derivative, for example using bis(trimethylsilyl) peroxide (see Scheme 14 below for an illustration of this method). A further process for the introduction of a group -P(O)(OH)2 is described in Australian patent application no. 54311/86, and involves the reaction of an amino, hydroxy or mercapto group with certain diesters of amides of phosphorus acid, followed by oxidation and hydrolysis of the resulting intermediate compounds.
Suitable reagents for the introduction of a solubilising group -NO2 are lower alkyl nitrates such as methyl nitrate or ethyl nitrate, and acyl nitrates such as acetyl nitrate or benzoyl nitrate.
Other methods for the preparation of compounds of formulae (I) to (IAW) referred to herein are disclosed in US Patent Nos. 5,116,835, 5,126,326; 5,132,400; 5,145,957; 5,198,426; 5,212,157; 5,215,968; 5,212,667; 5,294,720; and 5,296,604; International Patent Application Nos. 91/08221; 91/10442; 92/151319 and 92/21696; European Patent Application Nos. 0528242; 0519433 and 0432595 and Australian Patent Application Nos. 35700/89; 53716/90; 63221/90; 71319/91; 71320/91; 71323/91; 82313/91; 83206/91; 87594/91; 90531/91; 90851/94; 90925/91; 91251/91; 91332/91; 18355/92; 26424/92; 37160/93; 38808/93 and 44930/93, the disclosures of each of which are incorporated herein by reference.
A third embodiment of the invention is directed to pharmaceutical compositions comprising a compound of formula (I) together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients.
In a fourth embodiment of the invention there is provided a method for inhibiting retroviral proteases in a mammal in need of such inhibition, comprising administering to the mammal an effective amount of a compound of the first embodiment or of a composition of the second embodiment. In one form of the third embodiment, there is provided a method for the treatment or prophylaxis of HIV viral infections such as AIDS.
For inhibiting retroviral proteases or the treatment of HIV viral infections, a composition of the second embodiment may be administered orally, topically, parenterally, e.g. by injection and by intra-arterial infusion, rectally or by inhalation spray.
For oral administration, the pharmaceutical composition may be in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, including lyophilised powders, solutions, granules, suspensions, emulsions, syrups and tinctures. Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules.
Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.
Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinyl- pyrrolidone, sodium alginate or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.
The emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth.
For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, gel, jelly, tincture, suspension or emulsion. The pharmaceutical composition may contain pharmaceutically acceptable binders, diluents, disintegrating agents, preservatives, lubricants, dispersing agents, suspending agents and/or emulsifying agents as exemplified above. For parenteral administration, the compound of formula I or its salt may be prepared in sterile aqueous or oleaginous solution or suspension. Suitable non-toxic parenterally acceptable diluents or solvents include water, Ringer's solution, isotonic salt solution, 5% dextrose in water, buffered sodium or ammonium acetate solution, 1,3-butanediol, ethanol, propylene glycol or polyethylene glycols in mixtures with water. Aqueous solutions or suspensions may further comprise one or more buffering agents. Suitable buffering agents include sodium acetate, sodium citrate, sodium borate or sodium tartrate, for example. Aqueous solutions for parenteral administration are also suitable for administration orally or by inhalation.
For rectal administration, the compound of formula I is suitably administered in the form of an enema or suppository. A suitable suppository may be prepared by mixing the active substance with a non-irritating excipient which is solid at ordinary temperatures but which will melt in the rectum. Suitable such materials are cocoa butter, waxes, fats, glycerol, gelatin and polyethylene glycols. Suitable enemas may comprise agents as exemplified above with reference to forms for topical administration.
Suitably, an inhalation spray comprising a compound of formula I will be in the form of a solution, suspension or emulsion as exemplified above. The inhalation spray composition may further comprise an inhalable propellant of low toxicity. Suitable propellants include carbon dioxide or nitrous oxide.
The dosage form of the compound of formula I will comprise from 0.01 % to
99% by weight of the active substance. Usually, dosage forms according to the invention will comprise from 0.1 % to about 10% by weight of the active substance.
The compound of formula I may be administered together or sequentially with one or more other active substances known or believed to have anti- viral activity. Examples of such other active substances include AZT, acyclovir, ddC, ddA, trisodium phosphonoformate, castanospermine, rifabutin, ribaviran, bropirimine, phosphonothioate oligodeoxynucleotides, dextran sulfate, α-interferon and ampligen.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the transformation of the compound of Example 5 ("Prodrug") into the compound of Example 20 of International Patent Application No. PCT/AU93/00103 ("Drug") in rabbit's blood in vitro.
Figures 2 and 3 are graphs showing the transformation of Prodrug into Drug in vivo following intravenous and intramuscular (respectively) administration to a rabbit.
BEST MODE OF CARRYING OUT THE INVENTION
Methods for the preparation of compounds of formula (IB) wherein x and y are both O, B is -CH(OH)- and R506, R513, R542 and R543 are hydrogen are described in the following Schemes 11 and 12:
Figure imgf000081_0001
Figure imgf000081_0002
Scheme 13 presents an example of a method of preparation of Examples 11 and
12, commencing with the product of Scheme 12 in which R501 is benzyloxycarbonyl, R512 is methoxycarbonyl, R550 and R551 together form a 3,4-diazabicyclo[4.4.0]decane system and R502 is tert-butoxy carbonyl:
Figure imgf000082_0001
Scheme 14 presents an example of a method of preparation of compounds of formula shown in Table 4 below, in which the solubilising group Px is P(O)(OH)H or P(O)(OH)2:
Figure imgf000083_0001
Compositions of the third embodiment may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending, grinding, homogenising, suspending, dissolving, emulsifying, dispersing and mixing of the compound of formula (I) together with the selected excipient(s), carrier(s), adjuvant(s) and/or diluent(s).
In the method for the treatment of HIV viral infections in accordance with the fourth embodiment of the invention, a compound of the first embodiment will usually be administered orally or by injection. A suitable treatment may consist of the administration of a single dose or multiple doses of the compound of formula (I) or of a composition of the third embodiment. Usually, the treatment will consist of administering from one to five doses daily of the compound of formula (I) for a period of from one day to several years, up to the lifetime of the patient. Most usually, the treatment will consist of the administration of the compound of formula (I) for a period of from one day to one year.
The administered dosage of the compound of formula I can vary and depends on several factors, such as the condition of the patient. Dosages will range from 0.01mg to 200 mg per kg. Usually, the dose of the active substance will be from 0.01mg to 25 mg per kg of body weight.
Examples of dosage forms in accordance with the invention are as follows:
1. Tablet
Compound of formula I 0.01 to 20 mg, generally 0.1 to 10mg Starch 10 to 20 mg
Lactose 100 to 250 mg
Gelatin 0 to 5 mg
Magnesium stearate 0 to 5 mg
Capsule
Compound of formula I 0.01 to 20 mg, generally 0.1 to 10mg
Glycerol 100 to 200 mg
Distilled water 100 to 200 mg
Saccharin 0 to 2 mg
Methyl Paraben 1 to 2 mg
Polyvinylpyrrolidone 0 to 2 mg
Injectable solution
Compound of formula I 0.01 to 20 mg, generally 0.1 to 10mg
Sodium chloride 8.5 mg
Potassium chloride 3 mg
Calcium chloride 4.8 mg
Water for injection, q.s. to 10 ml
Elixir
Compound of formula I 0.01 to 20 mg, generally 0.1 to 10mg
Sucrose 100 mg
Glycerol 2ml
Carboxymethylcellulose 20mg
Cherry flavour 2 mg
Water q.s. to 10 ml
EXAMPLES
The following Examples describe the preparation of compounds according to the inventionand are intended to illustrate the invention. The Examples are not be construed as limiting in any way the scope of the present invention. Starting materials for the syntheses described in the following Examples are described in International Patent Application No. PCT/AU93/00103. In these Examples, melting points were taken on a hot stage apparams and are uncorrected. Proton and phosphorus NMR spectra were recorded at 100 MHz or 300MHz on Perkin Elmer R32 or Bruker EM 300 spectrometers, respectively, in CDCI3 unless otherwise stated. Chemical shifts for proton NMR are ppm downfield from tetramethylsilane; chemical shifts for P31 NMR are ppm downfield from l,2-bis(diphenylphosphino)ethane external standard. Thin layer chromotography (TLC) was performed on silica gel 60-F254 plates (Merck). Compounds were visualized by ultraviolet light and/or 2% aqueous potassium permanganate solution. The composition (by volume) of the TLC solvent systems were (A) hexane/ethyl acetate 3:2, and (B) concentrated NH4OH/isopropanol 1:3.
Example 1
4S,5S-5,6-Dibenzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-hydroxy-7-oxo-perhydro- 1,2,6-triazepine
Figure imgf000085_0001
Step A: 4S, 5S-5-benzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy-7-oxo- erhydro-1,2,6-triazepine: Hydrogen chloride gas was bubbled through the solution of 0.51 g (1.26 mmol) of. cis-1,6-3-t-butoxycarbonyl-4-[(2S,3S)-2-hydroxy-3-amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane (isomer having Rf (A) = 0.16 when eluted with 8% methanol in dichloromethane) in 10 ml of 1 % solution of methanol in methylene chloride for 30 min at room temperature. After purging the excess of hydrogen chloride with nitrogen gas the solvent was removed under reduced pressure to give 0.42 g (100% yield) of the hydrochloride salt of cis-1,6-4-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane as a hygroscopic, white solid. This was dissolved in 1 ml of dry DMF and 0.114 g (1.68 mmol) of imidazole and 0.21 g (1.38 mmol) of t-butyldimethylsilyl chloride were added under nitrogen. The resulting mixture was stirred overnight at room temperamre and evaporated to dryness in vacuo. The residue was diluted to 20 ml with ethyl acetate, washed with samrated sodium bicarbonate and dried over anhydrous potassium carbonate and filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 20 ml of dry dioxane. To this, 0.204 g (1.26 mmol) of 1,1'-carbonyldiimidazole was added and the resulting mixmre was stirred for 24 hrs at room temperamre. After evaporation of the solvent under reduced pressure the residue was diluted to 15 ml with ethyl acetate and washed with water (3x) and samrated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel; hexane/ethyl acetate 3:2) gave 0.095 g (17% yield) of the title compound, melting at 145 - 146°C; Rf (A) = 0.43; NMR 0.07, 0.09 (s,s 6H, CH3); 0.94 (s, 9H, t-butyl CH3); 1.2 - 2.0 (m, 10H, cyclohexane CH2, CH); 2.5 - 2.8 (m, 4H, CH2-3, benzyl CH2); 3.2 - 3.7 (m, 4H, dimethyl CH2); 3.9 - 4.0 (m, 3H, CH-4,5, NH); 7.1 - 7.32 (m, 5H, aromatic).
Step B: 4S, 5S-5, 6-dibenzyl-1, 2- (cis-1,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy- 7-oxo-perhydro-1,2,6-triazepine: 4.5 mg (0.15 mmol) of 80% dispersion of sodium hydride in mineral oil was added to a solution of 0.0665 g (0.15 mmol) of the product of Step A in 0.2 ml of dry DMF at room temperature. After stirring for 30 min at room temperamre, 0.0179 ml (0.15 mmol) of benzyl bromide was then added. The resulting mixmre was stirred overnight, then diluted to 15 ml with ethyl acetate and washed with water, samrated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography gave 0.029 g (36% yield) of the title compound as a heavy syrup; Rf (A) = 0.77; NMR -0.35, -0.18 (s, s, CH3); 0.8 (s, 9H, t-butyl CH3); 1.2 - 2.2 (m, 10H, cyclohexane CH2, CH); 2.56 - 4.18 (m, 12H, benzyl CH2, dimethyl CH2, CH2-3, CH-4,5); 6.8 - 7.4 (m, 10H, aromatic).
Step C: 4S, 5S-5, 6-Dibenzyl-1, 2- (cis-1, 2-cyclohexane)dimethyl-4-hydroxy- 7-oxo-perhydro-1,2,6-triazepine: A mixmre of 29 mg (0.0543 mmol) of the product of Step B and 0.0426 g (0.163 mmol) of tetrabutylammonium fluoride hydrate in 1 ml of anhydrous acetonitrile was stirred at 45±5°C for 3 hrs and evaporated to dryness. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate 3:2) to give 0.019 g (86% yield) of the title compound as a colourless foam; Rf (A) = 0.26; NMR 1.2 - 2.1 (m, 18H, cyclohexane CH2, CH, OH, 3.5 × H2O); 2.6 - 4.0 (m, 11H, benzyl CH2, dimethyl CH2, CH2-3, CH-5); 4.83 (m, 1H, CH-4); 7.0 - 7.4 (m, 10H, aromatic).
Example 2
4S,5S-l,5,6,Tribenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-1,2,6-triazepine
Figure imgf000086_0001
Step A: 4S, 5S-5-benzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-l, 2, 6-triazepine: When t-butyl 3-isopropyl-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]carbazate was substimted for cis-1,6-3-t-butoxycarbonyl-4-[(2S, 3S)-2-hydroxy-3-amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane in Step A of Example 1 the identical process afforded the title compound in 20% overall yield; melting point = 131 - 132°C (hexane); Rf (A) = 0.18; NMR 0.10, 0.11 (s, s, 6H, silyl CH3); 0.95 (s, 9H, t-butyl CH3); 1.1 - 1.35 (m, 6H, isopropyl CH3); 2.8 - 3.2 (m, 5H, CH2-3, CH-5, benzyl CH2); 3.45 (m, 1H, isopropyl CH); 4.18 (m, 1H, CH-4); 4.41 (m, 1H NH-6); 5.63 (s, 1H, NH-1); 7.1 - 7.4 (m, 5H, aromatic).
Step B: 4S, 5S-1, 5, 6-tribenzyl-2-isopropyl-4-t-butyldimethylsilyloxy- 7-oxo-perhydro-1 , 2, 6-triazepine: A mixture of 0.07 g (0.185 mmol) of the product of Step A and 0.012 g (0.371 mmol) of sodium hydride in 0.2 ml of dry DMF was stirred for 30 min at room temperature, then 0.0441 ml (0.371 mmol) of benzyl bromide was added. The resulting mixmre was stirred overnight and worked up as described in Step B of Example 1. The purification of the crude product by column chromatography (silica gel, hexane/ethyl acetate 3:2) gave 0.031 g (30% yield) of the title compound as a colourless syrup; Rf (A) = 0.74, NMR -0.28, -0.22 (s,s, 6H, silyl CH3); 0.8 (s, 9H, t-butyl CH3); 1.0 - 1.35 (m, 6H, isopropyl CH3); 2.35 - 3.3 (m, 5H, CH2-3, CH-5, 5-benzyl CH2); 3.45 - 3.82 (m, 2H, isopropyl CH, CH-4); 4.0 - 5.38 (m, 4H, 1,6-benzyl CH2); 6.6 - 7.8 (m, 15H, aromatic).
Also, the fractions with Rf (A) = 0.63 were combined and evaporated to dryness under reduced pressure to give 0.061 g (70% yield) of 4S,5S-5,6-dibenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepine as a colourless solid; NMR 0.11 (d, 6H, silyl CH3); 0.93 (s, 9H, t-butyl CH3); 1.24 (m, 6H, isopropyl CH3); 2.4 - 3.4 (m, 5H, CH2-3, CH-5, 5-benzyl CH2); 3.75 (m, 1H, isopropyl CH); 4.0 - 4.7 (m, 3H, CH-4, 6-benzyl CH2); 5.05 (m, 1H, NH); 7.0 - 7.7 (m, 15H, aromatic).
Step C: 4S, 5S-1,5, 6-Tribenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-1,2,6-triazepine: When the title compound of Step B was substimted for 4S,5S-5,6-dibenzyl-1,2-(cis-1,2-cyclohexane)-dimethyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepine in Step C of Example 1, the identical process afforded the title compound with 98 % yield as a foam; Rf (A) = 0.68; NMR (CDCl3) 1.07, 1.19 (d, d, 6H, isopropyl CH3); 1.58 (s, 1H, OH); 2.6 - 3.15 (m, 5H, CH2-3, CH-5, 5-benzyl CH2); 3.2 - 5.3 (m, 6H, isopropyl CH, CH-4, 1,6-benzyl CH2); 6.8 - 7.6 (m, 15H, aromatic).
Example 3
4S,5S-5,6-dibenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-1,2,6-triazepine
Figure imgf000087_0001
When 4S,5S-5,6-dibenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepine was substimted for 4S,5S-1,5,6-tribenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepine in Step C of Example 2 the identical process afforded the title compound in 88% yield; melting point = 191 - 193°C; Rf (A) = 0.17; NMR (DMSO-d6, 80°C) 2.5 - 3.0 (m, 4H, CH2-3, 5-benzyl CH2); 3.28 (m, 1H, CH-5); 3.6 (m, 1H, CH-4); 3.8 (m, 1H, isopropyl CH); 4.2 - 4.7 (m, 3H, 6-benzyl CH2; OH); 5.41 (m, 1H, NH); 7.0 - 7.4 (m, 10H, aromatic).
Example 4 t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl carbazate
Figure imgf000088_0001
To a mixmre of 0.4 g (0.67 mmol) of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3- (N-quinaldoyl-L-asparaginyl)amino-4-pheny lbutyl carbazate and 0.12 g (1.47 mmol) of anhydrous phosphorous acid in 1.5 ml of anhydrous pyridine was added 0.28 g (1.4 mmol) of dicyclohexylcarbodiimide at room temperamre under nitrogen, with stirring. After stirring for 2 hours at 60°C, the solvent was evaporated under reduced pressure and the residue was treated with 28 ml of 0.1 ml aqueous sodium bicarbonate and vigorously stirred for 1 hour at room temperamre. The precipitate was filtered off and washed with water and the filtrate was acidified to pH ~ 1.5 with concentrated hydrochloric acid. The product was taken up by extraction with ethyl acetate (3 x 50 ml), and the organic phase was dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.42 g (95% yield) of the title product as a colourless solid; Rf (B) = 0.62; H*NMR (CDCl3): 1.08 (m, 6H, isopropyl CH3); 1.41 (s, 9H, t-butyl CH3); 2.7 - 4.8 (m, 14H, asn CH2, butyl CH2-1, 4; CH-2,3; isopropyl CH; P-OH × 2H2O); 5.12 (m, 1H, asn CH); 5.89 (s, 0.5 H, PH); 6.2 - 8.5 (m, 15.5 H, aromatic, amide NH, 0.5 PH); 9.02 (m, 1H, asn NH); P31NMR (CDCl3) 14.99 (JP.H = 636 Hz). Example 5 t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl carbazate
Figure imgf000089_0001
A suspension of 0.4 g (0.6 mmol) of the product of Example 4 in 2 ml of hexamethyldisilazane was stirred for 45 min at 120 + 5°C. At this point the reaction mixmre became homogeneous. To this 0.3 ml of bis(trimethylsilyl)peroxide (Cookson, P.G et al., J. Organometal. Chem. , 1975, 99, C31) was added and stirring was continued for 1 hour at the above temperature. The reaction mixture was cooled to room temperamre, then evaporated to dryness in vacuo. The residue was dissolved in 20 ml of methanol, evaporated to dryness under reduced pressure and redissolved in 12 ml of 0.1 ml aqueous sodium bicarbonate. The resulting mixmre was acidified to pH ~ 1.5 with concentrated hydrochloric acid, samrated with sodium chloride and extracted with ethyl acetate (3 x 50 ml). The combined organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.39 g (96% yield) of the title compound as a colourless solid; Rf(B) = 0.07; H1NMR (CDCl3): 1.2 (m, 6H, isopropyl CH3); 1.4 (s, 9H, t-butyl CH3); 2.8 - 4.2 (m, 8H, asn CH2 butyl CH2-1,4, CH-3, isopropyl CH); 4.2 - 6.4 (m, 5H, asn CH, butyl CH-2, NH, POH); 6.5 - 8.4 (m, 14H, aromatic, NH); 8.78 (m, 2H, NH); P^lNMR (CDCl3) 9.6 (s).
Example 6 cis-1,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane
Figure imgf000090_0001
When cis-1,6-3-t-butoxycarbonyl-4-[(2S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane is substituted for t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutylcarbazate in Example 4, the identical process affords the title compound in 89% yield, as a colourless solid; Rf(B) = 0.64; H1NMR (CDCl3): 1.1 - 1.8 (m, 19H, t-butyl CH3, decane CH2-7,8,9,10, CH-1,6); 2.12 (m, 1H, butyl CH-3); 2.6 - 5.1 (m, 19H, asn CH2, CH, butyl CH2-1,4, CH-2, decane CH2-2,5, POH × 2.5 H2O); 6.1 - 8.4 (m, 15H, amide NH, PH, aromatic); 9.08 (m, 1H, asn NH); P31NMR (CDCl3) 16.43 (JPH = 700 Hz).
Example 7 cis-1,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane
Figure imgf000090_0002
When the product of Example 6 is substimted for t-butyl 3-isopropyl-3-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl carbazate in Example
5, the identical process affords the title compound in 83% yield, as a colourless solid; Rf(B) = 0.12; H1NMR (CDCl3): 1.1 - 2.4 (m, 20H, t-butyl CH3, decane CH2-7,8,9,10,
CH-1,6, butyl CH-3); 2.7 - 3.9 (m, 9H, asn CH2, butyl CH2-1,4, CH-2, decane CH2-5); 5.1 (m, 1H, asn CH); 6.1 - 8.3 (m, 21H, amide NH, aromatic, POH × 2.5 H2O); 9.05 (m, 1H, asn NH); P31NMR (CDCl3) 10.5 (s).
Other representative compounds in accordance with the invention are described in Tables 1 to 5. Other compounds in accordance with the invention are substances in which a hydroxyl, amino or mercapto group is any of the compounds described in the
Examples and disclosures of the following, has been derivatised with a solubilising group
Px as defined herein:
US Patent Nos. 5,116,835, 5,126,326; 5,132,400; 5,145,951; 5,198,426; 5,212,157; 5,215,968; 5,221,667; 5,250563; 5,268,361; 5,294,720; and 5,296,604; International Patent Application Nos. 90/09191; 91/08221; 91/10442; 92/15319 and 92/21696; European Patent Application Nos. 0574135; 0528242; 0519433 and 0432595 and Australian Patent Application Nos. 35700/89; 42308/89; 45665/89; 46115/89; 53716/90 63221/90; 66334/90; 71319/91; 71320/91; 71323/91; 77326/91; 81910/91; 82054/91 88900/91; 82313/91; 83234/91; 83206/91; 85877/91; 87309/91; 87409/91; 87594/91 88900/91; 89941/91; 90531/91; 90851/91; 90925/91; 91223/91; 91251/91; 91332/91 91790/92; 10812/92; 18355/92; 19373/92; 21944/92; 22889/92; 24129/92; 24690/92 26424/92; 31628/93; 35165/93; 35621/93; 37160/93; 38808/93; 41230/93; 41659/93 44930/93 and 49072/93, the disclosures of each of which are incorporated herein by reference. Example 8
In Vivo Removal of Phosphono Group
Solutions: The product of Example 5 was converted quantitatively into the corresponding disodium salt by treatment of the free acid with 2 equiv. of 0.2 M sodium bicarbonate and lyophilization of the resulting solution. The stock solutions of the disodium salt of the product of Example 5, for blood and animal experiments, were prepared in sterile water.
Analyses: Reverse phase analyses (HPLC) were performed on Waters ternary gradient liquid chromatograph equipped with 996 diode array detector set at 238 nm. Separations were achieved on Alltima RP-18 (250 × 4.6 mm, i.d., 5 μ particles), with the flow rate of 1 ml/min. The isocratic mobile phase composition used for analyses consisted of 40% of 0.1 % aqueous trifluoroacetic acid (TFA) and 60% of acetonitrile containing 0.1 % TFA and 10% water. The retention time of the product of Example 5 (referred to below as "Prodrug") was in the range of 3.6 - 3.9 minutes and the retention time of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl carbazate (referred to below as "Drug) was about 6.2 minutes. Detector response was linear from 0.5 to 120 μM for Prodrug and 0.05 to 50 μM for Drug. Standards and Sample Processing: The standards were prepared by serial dilution of Prodrug or Drug in rabbit blood collected into heparinised tubes. Blood samples were transferred into vials containing 150 units of heparin and stored on ice until processed. The blood samples were then separated by centrifuging at 6000 rpm for 10 min. The plasma samples were frozen and stored at -20°C until they were analysed.
Plasma preparation for HPLC analysis: An equal volume (100 μL) of thawed plasma and acetonitrile was stirred with a vortex mixer and allowed to stand at room temperature for 5 minutes, then centrifuged at 14000 rpm for 10 minutes. Samples of the supernantant (50 μL) were injected into the chromatograph. Transformation of Prodrug into Drug by Blood was established by measurement of prodrug and drug concentrations in plasma following the prodrug incubation in whole rabbit's blood (100 μM) at 36°C for 19 hours. Fig. 1 shows the concentrations of prodrug and drug under these conditions over 19 hours.
Transformation of Prodrug into Drug after intravenous (IV) administration of prodrug (9.2 mg/kg) to rabbit was established by measurement of prodrug/drug concentrations in plasma over 120 min. The formulated product, containing 30 mg/ml of prodrug, was well tolerated by the rabbit. The plasma profiles of prodrug and drug disappearance are shown in Fig. 2.
Transformation of Prodrug into Drug after Intramuscular (IM) administration of prodrug (7.9 mg/kg) to rabbit was established by measurement of drug concentrations in plasma over 330 min. The formulated product, containing 30 mg/ml of prodrug was well tolerated by the rabbit. The time dependence of the plasma concentration of the drug are shown in Fig. 3.
When prodrug was administered to a dog orally at a dose of 20mg/kg, the blood plasma concentration of drug was found to be 0.044, 0.141, 0.189, 0.172, 0.164, 0.132, 0.089 and 0.060 μM, respectively, after 5, 15, 30, 47, 63, 93, 124 and 155 minutes. When prodrug was administered to a second dog orally at a dose of 10mg/kg, the blood plasma concentration of drug was found to be 0.137, 0.371, 0.297, 0.242, 0.176, 0.11, 0.071, and 0.050 μM, respectively, after 5, 15, 30, 45, 60, 94, 123 and 154 minutes.
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
0
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
1. A compound of the general formula (I) or a pharmaceutically acceptable salt or prodrug thereof:
W-(A)n-B-(A*)m-V (I)
wherein
W is selected from the group consisting of R1-X-, R1*-X*-, -Y*, -CN, -N=CR5R5*, -C(R5)=NR3, -C(R5)=NOR3, -C(NR3R4)=NR5**, -C(D)OR3, -C(D)SR3 and -C(D)NR3R4, wherein
Y* is as defined below,
R1, R3 and R4 are independently selected from the group consisting of R6 and a solubilising group Px which is labile in vivo, wherein R6 is selected from the group consisting of
hydrogen,
R20, wherein R20 is selected from the group consisting of
optionally substituted (C1-C18)alkyl,
optionally substituted (C2-C18)alkenyl,
optionally substituted (C2-C18)alkynyl,
optionally substituted (C3-C18)cycloalkyl,
optionally substituted (C3-C18)cycloalkyl(C1-C18)alkyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substituted (Cg-C^aryl,
optionally substituted (C6-C24)aryl(C1-C18)alkyl,
optionally substituted (C6-C24)aryl(C2-C18)alkenyl, optionally substituted (C6-C24)aryl(C2-C18)alkynyl, optionally substituted (C1-C18)acyl,
optionally substituted heterocyclic,
optionally substituted heterocyclic(C1-C18)alkyl,
optionally substituted heterocyclic(C2-C18)alkenyl, and optionally substituted heterocyclic(C2-C18)alkynyl
C(D)OR21,
C(D)SR21,
C(D)NR21R22,
C(NR21)R22,
C(NR21)OR22, and
C(NR21)NR22R23, wherein R21, R22 and R23 independently are selected from hydrogen and R20 as previously defined, or R21 and R22 together, or R22 and R23 together form a

Claims

saturated or unsaturated cyclic, bicyclic or fused ring system as defmed herein,
or R3 and R4, when present, together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,
D is selected from O and S,
X is selected from the group consisting of Y, S(O) and S(O)2 wherein Y is as defined below,
X* is selected from the group consisting of NR10, O and S, wherein R10 has the meaning of R6 as previously defmed,
R1* is selected from the group consisting of R1 as previously defmed,
P(O)(OR7)R8, S(O)zOR7 and S(O)zNR7R8, wherein z is 1 or 2 and R7 and R6 independently have the meaning of R20 as previously defmed, or
R7 and R8 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,
R5 and R5* are independently selected from the group consisting of H, CF3, C(D)OR103, C(D)SR103 C(D)NR103R104 and R20 as previously defmed, wherein D is as previously defined, and wherein R103 and R104 have the meaning of R6 as previously defined, or R103 and R104 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and
R5** is selected from hydrogen and R20 as previously defined;
n is 0-6;
m is 0-6 and n+m≥ 1;
A at each occurrence is independently selected from the group consisting of
Figure imgf000147_0001
and a residue of a naturally occurring or synthetic amino acid;
A* at each occurrence is independently selected from the group consisting of
Figure imgf000148_0001
and a residue of a naturally occurring or synthetic amino acid; wherein
R12*, R13*, R9 and R9* are independently selected from the group consisting of F, Cl, Br, I and R5 as previously defined,
R11 has the meaning of R1 as previously defmed,
R12 has the meaning of R6 as previously defmed,
R13 is selected from the group consisting of
F, Cl, Br, I, R6 as previously defmed, and R200, wherein R200 is selected from the group consisting of
CN,
NCO,
NCS,
OCN,
SCN,
N3.
OR60,
SR60,
NR60R61,
D1C(D2)R60,
D1C(D2)D3R60,
D1C(D2)NR60R61,
NR60C(D1)R61,
NR60C(D1)D2R61,
NR60C(D1)NR61R62,
NR60OR61,
amidino,
guanidino,
S(O)R60,
S(O)2D 1R60,
S(O)NR60R61,
S(O)2NR60R61,
D1S(O)R60,
D1S(O)2OR60, D1S(O)NR60R61,
D1S(O)2NR60R61,
P(D1)(D2R60)R61,
P(D1)(D2R60)D3R61,
P(D1)(D2R60)NR61R62,
P(D1)R60R61,
D1P(D2)(D3R60)R61,
D1P(D2)(D3R60)D4R61,
D1P(D2)(D3R60)NR61R62,
D1P(D2)R60R61,
NR60NR61R62 and
ONR60R61, wherein D1, D2, D3 and D4 independently have the meaning of D as previously defmed, and R60, R61 and R62 independently have the meaning of Rβ as previously defmed or any two or more of R60, R61 and R62 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,
or R12 and R13 together are selected from the group consisting of =O, =S,
Figure imgf000149_0002
=NOR60, =NR60, -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (C1-C12)alkylidene as defmed herein and R60 is as previously defined, and
L is selected from the group consisting of a bond,
Figure imgf000149_0001
Figure imgf000150_0001
-CH2- and -CH2-CH2-, wherein R11 and D are as previously defined, R11* and D* have the meaning of R11 and D respectively, and z is 1 or 2;
R13** is F, Cl, Br, OR60 or NR60R60 wherein R60 and R61 are as previously defined,
B is selected from the group consisting of
Figure imgf000150_0002
wherein R203 and R203* independently have the meaning of R6 as previously defined, R14* and R14** are independently selected from the group consisting of hydrogen,
R20 as previously defined,
CF3,
C(D*)OR40,
C(D*)SR40 and
C(D*)NR40R41, wherein R40 and R41 independently have the meaning of
R21 and R22 as previously defined or R40 and R41 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,
R14 is selected from the group consisting of F, Cl, Br, I, R14* as previously defined and R200 as previously defined,
R17 and R17* independently have the meaning of R6 as previously defined,
D* has the meaning of D as previously defined,
Z is a saturated or unsaturated (C2-C4)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
Z* is a saturated or unsaturated (C1-C3)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
M1 is selected from the group consisting of OR15, SR15 and NR15R17, wherein R15 is selected from the group consisting of:
Px as previously defined,
R6 as previously defined,
Figure imgf000151_0003
Figure imgf000151_0001
,
Figure imgf000151_0002
, , wherein Px and D are as previously defined and R is H or C1-C4 alkyl, and
a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and
R17 is as previously defined, or
R15 and R17 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defined herein,
M and M* are independently selected from the group consisting of M1 as previously defined, OCN, SCN, YR2, Y* and N=CR30R31, wherein Y, Y* and R2 are as defmed below, and R30 and R31 independently have the meaning of R20 as previously defined, M2 is selected from the group consisting of R14* as previously defined, -CR30*=Y** and -CR30*=NR17*, where Y** is as defined below, R30* has the meaning of R20 as previously defined, and R17* is as previously defined,
R18 and R19 independently have the meaning of R20 as previously defined or
R18 and R19 together form part of a samrated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and
R18* and R19* together form part of a samrated or unsaturated cyclic, bicyclic or fused ring system as defined herein;
V is selected from the group consisting of YR2, Y* and C(R30)= Y**, wherein
Y is absent or is selected from the group consisting of:
Figure imgf000152_0001
wherein D** is selected from the group consisting of a bond, O, S and NR50, R50 has the meaning of R6 as previously defined, R51 has the meaning of R15 as previously defined and R52 has the meaning of R20 as previously defined, or R50 and R51, when present, together form part of a saturated or unsamrated cyclic, bicyclic or fused ring system as defined herein, and
R2 has the meamng of R6 as previously defined,
Y* is selected from the group consisting of o
Figure imgf000153_0001
, wherein D* and D** independently have the meaning of D as
Figure imgf000153_0002
previously defmed; R114*, R114**, R115 and R117* have the meaning of
Rl4*, R14**, R15 and R17* respectively, as previously defmed; R50 and R51 are as previously defined or R50 and R51 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein; R2* is selected from the group consisting of R2 as previously defined, Px as previously defined, S(O)zOR120 and S(O)zNR120R121, wherein z is 1 or 2;
R33 and R34 are independently selected from the group consisting of hydrogen and R20 as previously defined, or R33 and R34 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined herein, and R120 and R121 independently have the meamng of R20 as previously defined, or R120 and R121 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
R30 is as previously defmed, and
Y** is selected from =N-NR115R117 and =N-OR115, wherein R115 and R117 have the meaning of R15 and R6 respectively, as previously defined, or R1 15 and R117 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defined herein,
and wherein any group selected from R1 , R1*, R2, R2*, R9, R11, R12, R13, R50 and R51 may, together with any other group selected from R1, R1*, R2, R2*, R9*, R10, R11,
R12, R13, R50 and R51 form one or more samrated or unsamrated cyclic, bicyclic or fused ring system(s) as defined herein, and wherein any tertiary amino nitrogen atom may be replaced by the group
Figure imgf000154_0001
, and, wherein any hydroxyl, mercapto or amino group may be protected by a protecting group which is labile in vivo.
2. A compound according to claim 1, of the general formula (I') or a pharmaceutically acceptable salt or prodrug thereof:
W'-(A')n'-B'-(A'*)m'-V' (I')
wherein
W' is selected from the group consisting of R1-X-, R' 1*-X*-, -Y'*, -CN, -N=CR5R5*, -C(R5)=NR3, -C(R5)=NOR3, -C(D)OR3, -C(D)SR3 and -C(D)NR3R4, wherein
Y'* is as defined below,
R1, R3 and R4 are independently selected from the group consisting of R6 and a solubilising group Px which is labile in vivo, wherein R6 is selected from the group consisting of
hydrogen,
R20, wherein R20 is selected from the group consisting of
optionally substituted (C1-C18)alkyl,
optionally substituted (C2-C18)alkenyl,
optionally substituted (C2-C18)alkynyl,
optionally substituted (C3-C18)cycloalkyl,
optionally substituted (C3-C18)cycloalkyl(C1-C18)alkyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substimted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substituted (Cg-C24)aryl,
optionally substimted (C6-C24)aryl(C1-C18)alkyl,
optionally substimted (C6-C24)aryl(C2-C18)alkenyl, optionally substituted (C6-C24)aryl(C2-C18)alkynyl, optionally substituted (C1-C18)acyl,
optionally substituted heterocyclic,
optionally substituted heterocyclic(C 1-C18)alkyl,
optionally substituted heterocyclic(C2-C18)alkenyl, and optionally substituted heterocyclic(C2-C18)alkynyl
C(D)OR21,
C(D)SR21, and
C(D)NR21R22, wherein R21 and R22 independently are selected from hydrogen and R20 as previously defined, or R21 and R22 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, or R3 and R4, when present, together torm a saturated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
D is selected from O and S,
X is selected from the group consisting of Y', S(O) and S(O)2 wherein Y' is as defined below,
X* is selected from the group consisting of NR10, O and S, wherein R10 has the meaning of R6 as previously defmed,
R'1* is selected from the group consisting of Ri as previously defmed, S(O)zOR7 and S(O)zNR7R8, wherein z is 1 or 2 and R7 and R8 independently have the meaning of R20 as previously defined, or R7 and
R8 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defmed herein,
R5 and R5* are independently selected from the group consisting of H, CF3, C(D)OR103, C(D)SR103 C(D)NR103R104 and R20 as previously defined, wherein D is as previously defmed, and wherein R103 and R104 have the meaning of R6 as previously defined, or R103 and R104 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defined herein;
n' is 0-8;
m' is 0-8 and n' +m'≥ 1;
A' and A'* are independently at each occurrence selected from the group consisting of O, S, S(O), S(O)2, NR11, CR12R13 and CR12*R13*, or two consecutive groups A' -A' or A'*-A'* are a structural unit selected from
Figure imgf000155_0001
Figure imgf000155_0002
, wherein
and
R12*, R13*, R9 and R9* are independently selected from the group consisting of F, Cl, Br, I and R5 as previously defined,
R11 has the meaning of R1 as previosly defined,
R12 has the meaning of R6 as previously defmed,
R13 is selected from the group consisting of
F, Cl, Br, I, R6 as previously defined, and R200, wherein R200 is selected from the group consisting of
CN,
NCO,
NCS,
OCN,
SCN, N3.
OR60,
SR60,
NR60R61,
D1C(D2)R60,
D1C(D2)D3R60,
D1C(D2)NR60R61,
NR60C(D1)R61,
NR60C(D1)D2R61 )
NR60C(D1)NR61R62,
NR60OR61,
amidino,
guanidino,
S(O)R60,
S(O)2D1R60,
S(O)NR60R61,
SCOhNR60R61,
D1S(O)R60,
D1S(O)2OR60,
D1S(O)NR60R61,
D1S(O)2NR60R61,
P(D1)(D2R60)R61,
P(D1)(D2R60)D3R61,
P(D1)(D2R60)NR61R62,
P(D1)R60R61,
D1P(D2)(D3R60)R61,
D1P(D2)(D3R60)D4R61,
D1P(D2)(D3R60)NR61R62,
D1P(D2)R60R61,
NR60NR61R62 and
ONR60R61, wherein D1, D2, D3 and D4 independently have the meaning of D as previously defmed, and R60, R61 and R62 independently have the meaning of Rβ as previously defined or any two or more of R60, R61 and R62 form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
or R12 and R13 together are selected from the group consisting of =O, =S, =NOR60, =NR60, -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (C1-C12)alkylidene as defmed herein and R60 is as previously defined; selected from the group consisting of
Figure imgf000157_0001
wherein R203 and R203* independently have the meaning of R6 as previously defined,
R14* and R14** are independently selected from the group consisting of
hydrogen,
R20 as previously defined,
CF3,
C(D*)OR40,
C(D*)SR40 and
C(D*)NR40R4 1, wherein R40 and R41 independently have the meaning of R21 and R22 as previously defmed or R40 and R41 form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defmed herein, R14 is selected from the group consisting of F, Cl, Br, I, R14* as previously defined and R200 as previously defined,
R17 and R17* independently have the meaning of R6 as previously defined, D* has the meaning of D as previously defined,
Z is a saturated or unsaturated (C2-C4)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
Z* is a samrated or unsaturated (C1-C3)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R14* as previously defined,
M1 is selected from the group consisting of OR15, SR15 and NR15R17, wherein R15 is selected from the group consisting of:
Px as previously defined,
R6 as previously defined,
Figure imgf000158_0003
Figure imgf000158_0001
,
Figure imgf000158_0002
, , wherein Px and D are as previously defined and R is H or C1-C4 alkyl, and
a glycosyl radical which is derived from a synthetic or namrally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and
R17 is as previously defined, or
R15 and R17 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,
M and M* are independently selected from the group consisting of M1 as previously defmed, OCN, SCN, Y'R2, Y'* and N = CR30R31, wherein Y', Y'* and R2 are as defmed below, and R30 and R31 independently have the meaning of R20 as previously defined,
M2 is selected from the group consisting of R14* as previously defmed, -CR30*=Y** and -CR30*=NR17*, where Y** is as defmed below, R30* has the meaning of R20 as previously defined, and R17* is as previously defmed,
R18 and R19 independently have the meaning of R20 as previously defined or R18 and R19 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined herein, and
R18* and R19* together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined herein;
selected from the group consisting of Y'R2, Y'* and C(R30)=Y**, wherein Y' is selected from the group consisting of
Figure imgf000159_0001
wherein R50 has the meaning of R6 as previously defmed, R51 has the meaning of R15 as previously defined and R52 has the meaning of R20 as previously defmed, or R50 and R51 together form part of a samrated or unsamrated cyclic, bicyclic or fused ring system as defined herein, and
R2 has the meaning of R6 as previously defined,
Y'* is selected from the group consisting of
Figure imgf000160_0001
, wherein D* and D** independently have the meaning of D as
Figure imgf000160_0002
previously defined; R114*, R114**, R115 and R117* have the meaning of R14*, R14**, R15 and R17* respectively, as previously defined; R50 and R51 are as previously defined or R50 and R51 together form part of a samrated or unsaturated cyclic, bicyclic or fused ring system as defined herein; R2* is selected from the group consisting of R2 as previously defined,
S(O)zOR120 and S(O)zNR120R121, wherein z is 1 or 2; R33 and R34 are independently selected from the group consisting of hydrogen and R20 as previously defined, or R33 and R34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defmed herein, and R120 and R121 independently have the meaning of R20 as previously defined, or R120 and
R121 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
R30 is as previously defmed, and
Y** is selected from =N-NR115R117 and =N-OR115, wherein R115 and R117 have the meaning of R15 and R6 respectively, as previously defined, or
R115 and R117 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
and wherein any group selected from R1, R' 1*, R2, R2*, R9, R11, R12, R50 and R51 may, together with any other group selected from Rls R^*, R2, R2*, R9*, R10, R11, R12,
R50 and R51 form one or more saturated or unsamrated cyclic, bicyclic or fused ring system(s) as defmed herein, and wherein any tertiary amino nitrogen atom may be replaced by the group
Figure imgf000160_0003
, and, where the sequence W'-(A')n'-B'-(A'*)m'-V' contains a grouping of three heteroatoms together, one atom of those three heteroatoms is oxidised sulfur in the form of S(O) or S(O)2, or oxidised phosphorus in the form of P(O), or the three heteroatoms comprise two nitrogen atoms which form part of a heterocycle, provided that the sequence W,-(A,)n'-B'-(A'*)m'-V' does not contain two oxygen atoms together or three sulfur atoms together;
and wherein (a) when W is R'1*X* wherein X* is NR10, and V is Y'* wherein Y'* is
Figure imgf000161_0001
, and B' is or
Figure imgf000161_0003
Figure imgf000161_0002
wherein R81 is selected from the group consisting of hydrogen, -R100H,
-R100C(O)OR101, -R100C(O)NR101R102, -R100_NR102C(0)R100* and
-R100C(O)R100*,
wherein R101 and R102 are independently selected from the group consisting of hydrogen, optionally substituted (C1-C18)alkyl, optionally substituted (C3-C18)cycloalkyl, optionally substituted
(C3-C18)cycloalkyl-(C1-C18)alkyl, optionally substituted (C6-C24)aryl, optionally substituted (C7-C25)aralkyl, optionally substituted
(C2-C18)alkenyl, optionally substituted (C8-C26)-aralkenyl, optionally substimted (C2-C18)-alkynyl, optionally substimted (C8-C26)- aralkynyl and optionally substituted heterocyclic, and wherein R100 and R100* are independently divalent radicals derived from a member selected from the group consisting of (C1-C1g)alkyl,
(C3-C18)cycloalkyl, (C3-C18)cycloalkyl(C1-C18)alkyl, (C6-C24)aryl,
(C7-C25)aralkyl, (C2-C18)alkenyl, (C8-C26)aralkenyl, (C2-C18)alkynyl, (C8-C26)aralkynyl and heterocyclic, any of which may be optionally substimted as defined herein,
and R80 is selected from the group consisting of R81 as previously defined and a solubilising and/or protecting group Px which is labile in vivo, then at least one of the following applies:
(i) R50 is a group R53, wherein R53 is selected from the group consisting of
C(D*)OR21*, C(D*)NR21*R22*, C(D*)SR21*, C(D*)R55, CF3, R55 and a solubilising group Px which is labile in vivo, wherein
D* has the meaning of D as previously defined,
R21* and R22* have the meamng of R21 and R22 respectively, as previously defined,
and wherein R55 is selected from the group consisting of optionally substimted (C1-C18)alkyl(C6-C24)aryl, optionally substituted
(C2-C18)alkenyl(C6-C24)aryl, optionally substimted (C2-C18)alkynyl(C6-C24)aryl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substituted (C3-C18)cycloalkyl¬
(C6-C24)aryl, optionally substituted acyl(C6-C24)aryl, optionally substituted heterocyclic(C1-C18)alkyl, optionally substimted heterocyclic(C2-C18)alkenyl, optionally substituted heterocyclic(C2-C18)alkynyl and optionally substituted heterocyclic(C2-C18)- (C6-C24)aryl,
and n', m', R'1*, R10, A', A'*, R51 and R2* are as previously defined,
(ii) one of R2* and R51 is a group R54, wherein R54 is selected from the group consisting of R55*, C(D*)NR21*R22*, C(D*)OR55*, C(D*)R55*,
C(D*)SR21*, CF3, S(O)ZOR120, S(O)zNR120R121, and a solubilising group Px which is labile in vivo, wherein z is 1 or 2 and R120 and R121 are as previously defmed or R120 and R121 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined herein, and wherein R21* and R22* have the meaning of R21 and R22 respectively, as previously defmed, and R55* has the meamng of R55, as previously defined,
and n', m', R' 1*, R10, A', A'*, R50 and the other of R2* and R51 are as previously defined,
(iii) at least one A' or A'* is selected from the group consisting of CR112R13,
CR12R113, CR112R13* and CR12*R113, wherein R112 and R113 are independently selected from the group consisting of R55 as previously defined, C(D)OR21*, C(D)SR21*, C(D)NR21*R22*, F, Cl, Br and I, wherein R21* and R22* have the meaning of R21 and R22 respectively, as previously defined,
and D, n', m', R' 1*, R2*, R10, R11, R12, R12*, R13, R13*, R50 and R51 are as previously defined,
(iv) R'1* is selected from the group consisting of optionally substimted
(C2-C18)alkenyl, optionally substimted (C2-C18)alkynyl, optionally substimted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substituted
(C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substimted (C6-C24)aryl¬
(C2-C18)alkenyl, optionally substimted (C6-C24)aryl(C2-C18)alkynyl, optionally substituted (C2-C18)acyl, wherein the optional substiment is other than amino, optionally substituted (C6.C24)aryl(C2-C18)acyl, optionally substimted heterocyclic(C1-C18)alkyl, optionally substimted heterocyclic(C2-C18)alkenyl, optionally substituted heterocyclic(C2-C18)alkynyl, C(O)OR90, C(O)NR91R92, CF3, S(O)ZOR120, S(O)zNR120R121 and a solubilising group Px which is labile in vivo,
wherein z is 1 or 2 and R120 and R121 are as previously defined, wherein R90 is selected from the group consisting of (C3-C18)cycloalkyl, (C3-C18)cycloalkyl(C1-C18)alkyl, heterocyclic, (C1-C18)alkyl- heterocyclic, (C6-C24)aryl, (C6-C24)aryl(C1-C18)alkyl and
(C6-C24)aryl(C1-C18)alkylheterocyclic,
and wherein R91 and R92 are independently selected from the group consisting of optionally substimted (C2-C18)alkenyl, optionally substituted (C2-C18)alkynyl, optionally substimted
(C3-C18)cycloalkyl, optionally substimted (C3-C18)cycloalkyl(C1-C18)alkyl, optionally substimted (C3-C18)cycloalkyl(C2-C18)alkenyl, optionally substituted (C3-C18)cycloalkyl(C2-C18)alkynyl, optionally substimted (C6-C24)aryl(C2-C18)alkenyl, optionally substituted (C6-C24)aryl¬
(C2-C18)alkynyl, optionally substimted (C2-C18)acyl, optionally substituted (C6-C24)aryl(C2-C18)acyl, optionally substituted heterocyclic, optionally substituted heterocyclic(C1-C18)alkyl, optionally substituted heterocyclic(C2-C18)alkenyl, and optionally substimted heterocyclic(C2-C18)alkynyl, or R91 and R92 together form a samrated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
and m\ n', A', A'*, R2*, R50, R51 and R10 are as previously defined, (v) a group selected from Rl5 R'1*, R2, R2*, R9, R11, R12, R50 and R51, taken together with another group selected from R1 , R' 1*, R2, R2*, R9*, R10, R11,
R12, R50 and R51 is selected from the group consisting of -C(O)- and optionally substituted methylene;
(b) when W' is R'1*X* wherein X* is NR10, and V is Y'* wherein Y'* is
Figure imgf000163_0001
, and B' is selected from -CH(OH)- and -C(O)- then at least one of the following also applies when one of the conditions (i) to (iv) defined above in (a) applies:
(vi) n' > 1,
(vii) n' = 0,
(viii) m' > 1,
(ix) m' = 0,
(x) R50 and R51 together form part of a saturated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
(xi) R50 is a group R56, wherein R56 is selected from the group consisting of C(D*)OR21*, C(D*)NR21*R22*, C(D*)SR21*, C(D*)R55 and a solubilising and/or protecting group Px which is labile in vivo, wherein R21* and R22* are as previously defined, and
(xii) n' = m' = 1 and A'* is other than -CH2-, and (c) when B' is selected from
Figure imgf000164_0002
Figure imgf000164_0003
Figure imgf000164_0001
Figure imgf000164_0004
Figure imgf000164_0005
, , , ,
and
Figure imgf000164_0006
, wherein R14, R14* and R17 are as previously defined,
then at least one group selected from R2 or R2*, R11, R12, R50 and R51 together with another group selected from R1 , or R1*, R10, R11 and R12 forms a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, said ring being substimted with at least one polar group selected from =O, =S, OH, SH, NHR10* and C(O)OH, wherein R10* has the meaning of R10 as previously defined, said polar group being sterically capable of being located within the compound of formula (I) not more than 5 Ångstrom units from the P, O, S, N or C atom of group B,
provided that when W is R'1*X* and X* is NH and V' is Y'* wherein Y'* is
Figure imgf000164_0007
wherein R'1* is other than H and R71 and R72 are independently selected from the group consisting of H, (C1-C6)alkyl, optionally substituted phenyl, optionally substimted naphthyl, optionally substituted phenyl(C1-C2)alkyl and optionally substimted naphthyl¬
(C1-C2)alkyl, and when
(a) B' is -CH(OH)- and (A')n is -CH(R73)- wherein R73 is selected from the group consisting of (C1-C6)alkyl optionally substimted with 1-5 fluorine atoms, (C3-C6)alkenyl, (C1-C6)alkoxy-CH2-, (CH2)pphenyl, (CH2)pnaphthyl,
(CH2)p(C5-C6)cycloalkyl and (CH2)pindolyl, wherein said (CH2)nphenyl,
(CH2)nnaphthyl, (CH2)n(C5-C6)cycloalkyl and (CH2)nindolyl are optionally substituted with nitro, halogen, (C1-C4)alkyl, (C1-C4)alkoxy or
(C1-C4)alkylthio and wherein p is 0, 1 or 2, then (A'*)m' is other than wherein R74 has the meaning of R73 as previously defined, and
Figure imgf000164_0008
when
(b) B' is wherein R74 has the meaning of R73 as previously defined and
Figure imgf000164_0009
(A')n- is wherein R73 is as previously defmed, then (A'*)m' is
Figure imgf000164_0010
other than -C(O)-, and when (c) B' is -C(O)- and (A')n ' is wherein R73 is as previously
Figure imgf000165_0002
defined, then m' is other than 0.
3. A compound according to claim 1, wherein B is selected from the group consisting of
Figure imgf000165_0001
where Z, Z*, M, M1, M2, D*, R14, R14*, R14**, R15, R18, R18*, R19 and R19* are as defined in claim 1,
V is YR2, Y* or C(R30)=Y**, wherein R2, R30 and Y** are as defined in claim 1, Y is selected from the group consisting of and
Figure imgf000165_0003
Y* is selected from the group consisting of
Figure imgf000165_0004
Figure imgf000165_0005
and
Figure imgf000165_0006
, wherein R33, R34, R50, R51 and R2* are as defined in claim 1.
4. A compound according to claim 1 having the strucmre represented by formula
(IA):
Figure imgf000165_0007
wherein R1*, R10, R12, R12*, R13 and R13* are as defined in claim 1,
B* is selected from the group consisting of
Figure imgf000166_0001
where Z, Z*, M, M1, M2, D*, R14, R14*, R14**, R18 and R19 are as defined in claim 1, and
Yl is selected from the group consisting of
Figure imgf000166_0004
,
Figure imgf000166_0005
and
Figure imgf000166_0006
wherein R50, R51 and R2* are as defined in claim 1.
5. A compound according to claim 1 of the general formula (IB):
Figure imgf000166_0002
wherein x and y are independently 0 or 1 ,
B is selected from the group consisting of
Figure imgf000166_0003
wherein R14*, R14**, R15, R18 and R19 are as defined in claim 1 and each R560 is independently hydrogen or (C1-C4)alkyl,
R502 and R506 are independently a group R600, wherein R600 is selected from the group consisting of hydrogen, C(O)OR621, C(O)SR621, C(O)NR621R622, (C1- C6)alkyl, (C2-C6)alkenyl, (C5-C10)cycloalkyl, (C5-C10)cycloalkyl(C1- C6)alkyl, (C5-C10)cycloalkyl(C2-C6)alkenyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, (C1-C6)acyl, heterocyclic, heterocyclic(C1-C6)alkyl and heterocyclic(C2-C6)alkenyl, each of which may be substimted by up to three substiments selected from the substituents defined herein for "optionally substimted (C1-C18)alkyl" and R621 and R622 have the meaning of R21 and R22 respectively, as defmed in claim 1, or R621 and R622 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defined below,
R501 is selected from the group consisting of R6oo as previously defined,
S(O)OR632, S(O)2R632, S(O)NR632R633, S(O)2R632R633, NH2, NHR631 and NR631R632, wherein R631 has the meaning of R6 as defined in claim 1 and R632 and R633 independently have the meaning of R20 as defined in claim 1, or R501 and R506 together form part of a saturated or unsamrated cyclic, bicyclic or fused ring system, or R631 and R632, or R632 and R633 together form a saturated or unsamrated cyclic, bicyclic or fused ring system as defined herein,
R512 and R542 independently have the meaning of R600 as previously defined,
R522 and R532 are independently selected from the group consisting of R600 as previously defmed, F, Cl, Br and I,
R5l3 and R543 are independently selected from the group consisting of R600 as previously defined and R20o as defined in claim 1,
R523 and R533 are independently selected from the group consisting of R600 as previously defined, F, Cl, Br, I, and R20o as defined in claim 1,
R550 has the meaning of R6 as defined in claim 1 and R55 1 is selected from the group consisting of R650, hydrogen, S(O)OR632, S(O)2R632, S(O)NR632R633 and S(O)2R632R633, wherein R650 has the meaning of R6 as defined in claim 1 and R632 and R633 are as previously defmed, or R632 and R633 together form a samrated or unsaturated cyclic, bicyclic or fused ring system as defined herein, or R550 and one of R551 and R502 together form a diazaheterocycle wherein R550, R551 or R502 and the two nitrogen atoms to which they are bonded are part of a stable 5 to 10-membered ring which may comprise up to two further heteroatoms selected from O, S and N and to which may be fused one or more cycloalkyl, cycloalkenyl, aryl or heterocyclic residues, which diazaheterocycle may be substimted by one or more of the substiments defmed herein for "optionally substimted (C1-C18)alkyl", and wherein two substiments may together form part of a ring,
or one pair selected from R512 and R513, R522 and R523 (when present), R532 and
R533 (when present), and R542 and R543, together are =O; wherein, when B is other than or then at least one of conditions
Figure imgf000167_0001
Figure imgf000167_0002
(i) to (xi) below applies:
(i) at least one of R512 and R542 is a group R655, wherein R655 is selected from the group consisting of (C1-C6)alkyl(C6-C10)aryl, (C2-C6)alkenyl(C6-C10)aryl, (C5-C10)cycloalkyl(C2-C6)alkenyl, (C5-C10)cycloalkyl(C6-C10)aryl, acyl(C6- C10)aryl, heterocyclic(C1-C6)alkyl, heterocyclic(C2-C6)alkenyl, heterocyclic- (C6-C10)aryl, C(D*)OR21*, C(D*)SR21* and C(D*)NR21*R22*, wherein D*,
R21* and R22* are as defined in claim 1,
(ii) at least one of R522 and R532, when present, is selected from the group consisting of R655 as previously defined, F, Cl, Br and I,
(iii) at least one of R513 and R543, when present, is selected from the group consisting of R655 as previously defined, and R200 as defined in claim 1 ,
(iv) at least one of R523 and R533, when present, is selected from the group consisting of R655 as previously defined, F,Cl Br, I and R200 as defined in claim 1,
(v) R550 is a group R656, wherein R656 is selected from the group consisting of
(C1-C6)alkyl(C6-C10)aryl, (C2-C6)alkenyl(C6-C10)aryl, (C5-C10)cycloalkyl¬
(C2-C6)alkenyl, (C5-C10)cycloalkyl(C6-C10)aryl, acyl(C6-C10)aryl, heterocyclic(C1-C6)alkyl, heterocyclic(C2-C6)alkenyl, heterocyclic(C6-C10)aryl,
(vi) R551 is selected from the group consisting of R656 as previously defmed,
S(O)OR632, S(O)2R632, S(O)NR632R633 and S(O)2R632R633, wherein R632 and R633 are as previously defined,
(vii) R502 is selected from the group consisting of R65g as previously defined, C(D*)SR21* and C(D*)NR21*R22*, wherein D*, R21* and R22* are as defined in claim 1,
(viii) R502 and R551 are both hydrogen or are both (C1-C6)acyl,
(ix) R14* is selected from the group consisting of C(D*)OR40, C(D*)SR40 and
C(D*)NR40R41, wherein R40 and R41 are as previously defmed,
(x) R501 is selected from the group consisting of R656 as previously defmed,
S(O)OR632, S(O)2R632, S(O)NR632R633, S(O)2R632R633, NH2, NHR631 and
NR631R632, wherein R632 and R633 are as previously defined,
(xi) R501 and R506 are both (C1-C6)acyl, and wherein when B is or then at least one of the following
Figure imgf000168_0001
Figure imgf000168_0002
conditions also applies:
(xii) x + y > 0,
(xiii) x + y = 0 and at least one of R532 and R533 is other than hydrogen, (xiv) R50 and R51 together form a diazaheterocycle as previously defined, (xv) at least one of R501, R502, R5O6 and R551 is optionally substimted heterocyclic(C1-C18)alkyl, and (xvi) at least one of R512, R542, R522, R532, R513, R543, R523 and R533 is selected from the group consisting of C(O)OR621, C(O)SR621 and
C(O)NR621R622, wherein R621 and R622 are as previously defmed.
A compound according to claim 1 comprising at least one solubilising group Px,
wherein Px is selected from the group consisting of Px*,
Figure imgf000169_0001
,
Figure imgf000169_0003
,
Figure imgf000169_0002
, and wherein D is O or S, R is H or C1-C4 alkyl, and wherein
Px* is selected from:
Figure imgf000169_0004
or, wherein the compound of formula (I) as defined in claim 1 includes two functional groups capable of being derivatised by a solubilising group Px, said two functional groups being in sufficiently close proximity to one another, comprising a cyclic structure including a structural unit selected from:
Figure imgf000169_0005
wherein X1 and X2 are independently selected from O, S and NR6 wherein R6 is as defined in claim 1.
7. A compound according to claim 6 wherein said solubilising group is selected from
Figure imgf000170_0001
and
Figure imgf000170_0002
.
8. A compound according to claim 1, selected from the group consisting of formula (IC) to (IAW), wherein each AA is independently a residue of a namrally occurring or synthetic amino acid as herein defined; R1*, R1, X and X* are as defined in claim 1; Ra to Rj independently are -(CH2)a-6OPy or R6, wherein a can be 0, 1, 2, 3, 4 or 5, and wherein Py is a solubilising group Px as defined herein, and R6 is as defined in claim 1 :
Figure imgf000170_0003
wherein D' is O or S, and each G is independently hydrogen or R200 as defined in claim 1 and wherein R'd and R'f are Rd and Rf or, taken together, may be trimethylene or tetramethylene optimally substituted with -C(O)OR; or -C(O)NRiRj;
Figure imgf000170_0004
wherein G is selected from R1* and X*R1*;
Figure imgf000170_0005
wherein Ra' is OPy or R6 as defined in claim 1, M1 is R6 as defined in claim 1, (CH2)1- 2OPy or (CH2)1-2NHPy, and G* is OR2 or NRiR2;
Figure imgf000171_0001
;
Figure imgf000171_0002
wherein G is hydrogen, Ra, R1*X* or R1*X*C(Ra)(Rb)C(O), and wherein Ra, R1*, and the atoms to which they are bound may optionally form a samrated or unsamrated cyclic, bicyclic or fused ring system;
Figure imgf000171_0003
wherein Ra, R1*, and the atoms to which they are bound may optionally form a saturated or unsamrated cyclic, bicyclic or fused ring system;
Figure imgf000171_0004
wherein W2 is R1X or R6 as defined in claim 1, and R' is Py or R6 as defmed in claim 1, or R' and Py, taken together with the oxygen atoms to which they are attached form a group selected from , and ;
Figure imgf000171_0005
Figure imgf000171_0006
Figure imgf000171_0007
Figure imgf000172_0001
wherein each L is independently as defined in claim 1 and each Pz is independently hydrogen or Py, provided that at least one Pz is Py or, when each Pz is Py, the groups
Py, together with the oxygen atoms to which the are bound define a cyclic group selected from , and ;
Figure imgf000172_0002
Figure imgf000172_0003
Figure imgf000172_0004
Figure imgf000172_0005
wherein Q is O or NRf and G is R1* or X*R1*;
Figure imgf000172_0006
wherein each is independently a 5- or 6- membered samrated or unsamrated
Figure imgf000172_0008
heterocycle containing a nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, oxygen and sulfur, and wherein Ra' and Rb' independently have the meaning of -(CH2)0-6OPy or R6, or taken together are = O; .
Figure imgf000172_0007
wherein W1 is selected from R1X and R1*X*, and Q is selected from O and NRh;
Figure imgf000173_0001
wherein W1 is selected from R1X and R1*X*, each Pz is independently hydrogen or Py, provided that at least one Pz is Py, and Q is selected from O and NRh;
Figure imgf000173_0002
wherein each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
Figure imgf000173_0003
wherein is a 5- or 6- membered samrated or unsamrated heterocycle containing a
Figure imgf000173_0004
nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, oxygen and sulfur;
Figure imgf000173_0005
wherein Ra' and Rj' are independently selected from R1 and R 1*, as defined in claim 1;
Figure imgf000174_0001
wherein G is selected from , and a saturated or unsaturated
Figure imgf000174_0002
Figure imgf000174_0003
cyclic, bicyclic or fused ring system, Q is O or NH, and G* is X or X* as defined in claim 1;
Figure imgf000174_0004
wherein is a 5-12 membered samrated or unsaturated cyclic, bicyclic or fused
Figure imgf000174_0007
ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur;
Figure imgf000174_0005
wherein G is selected from hydrogen and R1*X*, Q is O, S or NH, Q* is O or NH, and G1 is selected from R1 and R1*X*;
Figure imgf000174_0006
wherein R200 is as defined in claim 1;
Figure imgf000175_0001
wherein is an optionally substituted 5-12 membered samrated or unsamrated
Figure imgf000175_0002
cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from mtrogen, oxygen and sulfur;
Figure imgf000175_0003
wherein b is 0, 1 or 2, provided that at least one b is greater than 0, and each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
Figure imgf000175_0004
wherein each G* is independently selected from O, S and NR6 and G is selected from OR6, NHR6 and R20;
Figure imgf000175_0005
wherein G is -C(O)- or -CH2-, G* is R1 or R1*, G** is -O- or -NRh-, Q is -O- or -NRi and Pz is selected from the group consisting of ,
Figure imgf000175_0007
,
Figure imgf000175_0008
,
Figure imgf000175_0009
,
Figure imgf000175_0006
Figure imgf000176_0001
wherein R and R' are independently hydrogen or C1-C4 alkyl, D is O or S and Px* is as defined herein;
Figure imgf000176_0002
wherein G is R1 or R1*, G* is -O- or -NRf- and Pz is selected from the group consisting
Figure imgf000176_0003
wherein R and R' are independently hydrogen or C1-C4 alkyl, D is O or S and
Px* is as defmed herein;
Figure imgf000176_0004
wherein G is R1 or R1*, and each Q is independently H, -OPz or -NRdPz, wherein each Pz is independently hydrogen or Py, provided that at least one Pz is Py;
Figure imgf000177_0001
wherein is a samrated or unsamrated cyclic, bicyclic or fused nitrogen
Figure imgf000177_0002
containing ring system and G is a bond or is -O- or -NRf;
Figure imgf000177_0003
wherein G is absent or X*R1* and is a 3 to 10-membered saturated or unsaturated
Figure imgf000177_0004
heterocycle containing a nitrogen atom and optionally additionally one to three heteroatoms selected from nitrogen, oxygen and sulfur;
Figure imgf000177_0005
wherein Q is selected from -O-, -S- and -NRf-;
Figure imgf000177_0006
wherein G is O, S, S(O) or S(O)2, and Ra' and Rb' have the meaning of Ra and Rb or Ra' and Rb' together are trimethylene or tetramethylene;
Figure imgf000177_0007
wherein each Ar is independently (C6-C14)aryl, R'c and R'd are Rc and Rd or, taken together, are -C(O)- or -CH(OH)-, and wherein Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from
Figure imgf000178_0001
,
Figure imgf000178_0002
and
Figure imgf000178_0003
;
Figure imgf000178_0012
wherein G is a bond or X as defined in claim 1, Rg' and Rh' are Rg and Rh or together form a samrated or unsaturated cylic, bicylic or fused ring system, and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from
Figure imgf000178_0004
,
Figure imgf000178_0005
and
Figure imgf000178_0006
.;
Figure imgf000178_0011
wherein G is a bond, O, S or NRj, Rg' and Rh' are Rg and Rh, or taken together may be -C(O)-, and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected from
Figure imgf000178_0007
,
Figure imgf000178_0008
and
Figure imgf000178_0009
;
Figure imgf000178_0010
wherein G is OPy, NHRe, NPyRe or Re;
Figure imgf000179_0001
wherein G and G* are independently a bond, O, S or NH, and R'd and Rh' are Rd and Rh or taken together are -CR'2- or -CR2'-CR2'- wherein each R' independently has the meaning of R6 as defined in claim 1, Q and Q* are independently N or CR6, or when Q* is CR6 then Rg and R6 together may be a double bond;
Figure imgf000179_0002
wherein G is -C(O)- or -C(R6)(CH2)0-4OG* wherein G* is R6 or Py;
Figure imgf000179_0003
;
Figure imgf000179_0004
wherein G is selected from hydrogen and X*R1* and wherein represents a 4-10
Figure imgf000179_0005
membered samrated or unsamrated cyclic, bicylic or fused ring system as defined herein;
Figure imgf000179_0006
wherein Q is selected from O, S and NRg, G and G* are independently selected from R1, R1*, -C(R5)=NR3 and -C(R5)=NOR3, wherein R3 and R5 are as defined in claim 1, R'e and R'f are Re and Rf, and G** is R20 as defined in claim 1;
Figure imgf000180_0001
wherein each Rz is independently selected from R1 and PyOG* wherein G* is optionally substimted alkylelne, provided that at least one Rz is PyOG*, and G is -NRd- or CRdRe-;
Figure imgf000180_0002
wherein
Figure imgf000180_0003
represents an optionally substimted samrated or unsamrated ring system optionally containing up to three heteroatoms selected from N, O and S, G is selected from R1 , XR1 or X*R1* and Ra and Rb taken together may optionally be -C(O)-;
Figure imgf000180_0004
wherein B* is a group B, as previously defeined, derivatised with a solubilising group Py;
Figure imgf000180_0005
wherein
Figure imgf000180_0006
represents an optionally substituted cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 3 heteroatoms selected from N, O and S;
Figure imgf000181_0001
wherein Q1 and Q2 are independently selected from O and S, and R'f and R'g are respectively Rf and Rg or are selected from OR', SR' and NRhR' wherein R' is H, Ri or
Py;
Figure imgf000181_0002
wherein each G is independently selected from O and NRi, and R' is (CH2)1-2OPy or R6;
Figure imgf000181_0003
wherein G and G* are independently selected from
Figure imgf000181_0004
and L, wherein L is as defined in claim 1 and Q is H or Py, provided that at least one of G and G* is other than L and provided that at least one Q is Py, or wherein two groups OQ taken together are a cyclic group sleeted from
Figure imgf000181_0005
, and
Figure imgf000181_0006
;
Figure imgf000181_0007
wherein Rx and Ry are independently R6 or (CH2)1 -2OPy;
Figure imgf000182_0001
wherein G and G* are independently selected from R1, R1*, -C(R5)=NR3 and -C(R5)N=OR3, wherein R3 and R5 are as defined in claim 1.
9. A compound according to claim 1 selected from the group consisting of
(i) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phenylbutyl]carbazate,
(ii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L- valyl)amino-4-phenylbutyl]carbazate,
(iii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]carbazate,
(iv) t-butyl 3-(1-methyl-3-phenylpropen-3-yl)-3-[(2R or S,3S)-2-hydroxy-3- (phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate,
(v) t-butyl 3-(1-methyl-3-phenylpropyl)-3-[(2R or S,3S)-2-hydroxy-3-(N- quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]carbazate,
(vi) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-amino-4- phenylbutyl]-3,4-diazabicyclo[4.4.0]decane,
(vii) cis-1, 6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-diazabicyclo[4.4.0]decane,
(viii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L- valyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane
(ix) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-[N-(2-pyridyl)- methoxycarbonyl)-L-valyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane
(x) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane,
(xi) cis-1, 6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L- glutaminyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane,
(xii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L- threonyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane, (xiii) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]hept-5-ene,
(xiv) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1]heptane,
(xv) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(2-pyridyl)methoxy-L- valyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1]heptane, (xvi) 2-[N-(1S)(2-methyl-1-methoxycarbonylpropyl)carbamoyl]-3-[(2R or S, 3S)- 2-hydroxy-3-[N-(2-pyridyl)methoxy-L-valyl]amino-4-phenylbutyl]-2,3- diazabicyclo[2.2.1]heptane,
(xvii) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]heptane,
(xviii) 1-[2-(2-pyridyl)methoxycarbonylamino-]benzoyl-2-[(2R or S,3S)-2- hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl]-2-isopropylhydrazine,
(xix) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-1,2,3,4-tetrahydrophthalazine,
(xx) 1-trimethylacetyl-2-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phyenylbutyl]-2-isopropylhydrazine,
(xxi) 1-trimethylacetyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl) amino-4-phenylbutyl]-2-isopropylhydrazine,
(xxii) 1-(t-butylamino)carbonyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-2-isopropylhydrazine,
(xxiii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-picolinoyl-L- asparaginyl)amino-4-phenylbutyl]carbazate,
(xxiv) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(2-pyridyl)-methoxycarbonylanthraniloyl)amino-4-phenylbutyl]carbazate.
(xxv) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phenylbutyl]carbazate,
(xxvi) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)- amino-4-phenylbutyl]carbazate,
(xxvii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenyl-methoxycarbonyl)amino-4-phenylbutyl]carbazate,
(xxviii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]carbazate,
(xxix) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(1-carbamoyl-methyl)- acryloyl)amino-4-phenylbutyl]carbazate,
(xxx) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio- 2-carbamoyl-methylpropionyl)amino-4-phenylbutyl]carbazate,
(xxxi) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(1-benzoyl-L- asparaginyl)amino-4-phenylbutyl]carbazate,
(xxxii) 1-t-butyloxycarbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]hexahydropyridazine,
(xxxiii) 1-t-butyloxycarbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]hexahydropyridazine, and
(xxxiv) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-3- cyano-L-alanyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4,4,0]decane, wherein the 2-hydroxy group has been derivatised with a solubilising group Px as herein defined.
10. A compound acording to claim 9, wherein said solubilising group is selected from
Figure imgf000184_0001
and
Figure imgf000184_0002
.
11. A compound according to claim 10, which compound is selected from the group consisting of:
cis-1,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane; cis-1,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane; t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-L-asparaginyl)- amino-4-phenylbutylcarbazate and
t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-L- asparaginyl)amino-4-phenylbutylcarbazate.
12. A process for preparing a compound of formula (I) according to claim 1, said process being selected from the group consisting of:
(a) reacting a compound W-(A)n-B-(A*)m-G with a compound H-V;
(b) reacting a compound W-(A)n-B-(A*)m-H with a compound G-V;
(c) reacting a compound W-H with a compound G-(A)n-B-(A*)m-V; and (d) reacting a compound W-G with a compound H-(A)n-B-(A*)m-V;
wherein G is a leaving group; optionally in the presence of a strong base and/or a coupling agent.
13. A process for preparing a compound of formula (IB) according to claim 3 wherein B is a substimted carbon atom and y is 0, said process being selected from:
(a) wherein x is 1, reacting a compound of formula (IIA), (IIB) or (IIC)
Figure imgf000184_0003
with a compound of formula (III)
Figure imgf000185_0001
and
(b) wherein x is 0, reacting a compound of formula (IIC) or (IID)
Figure imgf000185_0002
with a compound of formula (III) as previously defmed.
14. A process for enhancing the water-solubility of a pharmaceutical or veterinary substance, comprising derivatising a functional group of said substance with a solubilising
group Px, wherein Px is selected from the group consisting of Px*,
Figure imgf000185_0003
Figure imgf000185_0005
Figure imgf000185_0004
, and wherein D is O or S, R is H or C1-C4 alkyl, and wherein Px* is selected from:
O
Figure imgf000185_0006
Figure imgf000186_0001
said functional group being capable of being derivatised with said solubilising group Px.
15. A process according to claim 14 wherein said substance is an HIV protease inhibitor.
16. A process according to claim 14 wherein said solubilising group Px is selected from
Figure imgf000186_0002
17. A process according to claim 14 comprising reacting a hydroxyl group of said substance with phosphorous acid and optionally oxidising the product so obtained.
18. The product of the process of claim 12.
19. The product of the process of claim 14.
20. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 11, 18 or 19 together with at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
21. A process for preparing a pharmaceutical composition according to claim 20, comprising mixing a compound according to any one of claims 1 to 11, 18 or 19 with at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
22. A method for the treatment or prophylaxis of a retroviral infection, comprising administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of a compound according to any one of claims 1 to 11, 18 or 19, or of a composition according to claim 20.
23. A method according to claim 22 wherein said retroviral infection is AIDS.
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